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Antibody-Drug Conjugates: Possibilities and Challenges.

Mohammad-Reza Nejadmoghaddam, Arash Minai‐Tehrani, Ramin Ghahremanzadeh and 3 more

PubMed · 2019 · Review

Abstract

The design of Antibody Drug Conjugates (ADCs) as efficient targeting agents for tumor cell is still in its infancy for clinical applications. This approach incorporates the antibody specificity and cell killing activity of chemically conjugated cytotoxic agents. Antibody in ADC structure acts as a targeting agent and a nanoscale carrier to deliver a therapeutic dose of cytotoxic cargo into desired tumor cells. Early ADCs encountered major obstacles including, low blood residency time, low penetration capacity to tumor microenvironment, low payload potency, immunogenicity, unusual off-target toxicity, drug resistance, and the lack of stable linkage in blood circulation. Although extensive studies have been conducted to overcome these issues, the ADCs based therapies are still far from having high-efficient clinical outcomes. This review outlines the key characteristics of ADCs including tumor marker, antibody, cytotoxic payload, and linkage strategy with a focus on technical improvement and some future trends in the pipeline.

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Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Similar to conventional cancer treatments such as chemotherapy and radiotherapy, antibody immunotherapy and targeted therapies based on nanoparticulate structures are not safe and efficacious as often claimed; therefore, alternative therapies are urgently needed. In this regard, Antibody Drug Conjugates (ADC) technology that could bring forth a new generation of cancer therapeutics was the main focus of this study. ADCs are monoclonal antibodies (mAbs) connected by a specified linkage to antitumor cytotoxic molecules. The main components of an ADC and mechanism of its action are further demonstrated in figure 1.

In ADC technology, the specificity of an antibody for its immunogenicity is exploited to home a chemically supertoxic agent into tumor cells, while administration of unconjugated drug alone is not suitable due to its high toxicity. Therefore, ADCs can be further defined as prodrugs requiring the release of their toxic agent for their activation that commonly happens after ADC internalization into the target cell. From the standpoint of nanomedicine, the antibody in ADC structure acts as a self-targeting nanoscale carrier –, thus, it could overcome the issues associated with nanomedicines based on synthetic nanomaterials such as cellular internalization, clearance, sterical hindering of binding to the epitopes and failing to release into targeted cells.

The first experimental design on ADC subject dates back to more than 50 years ago. However, the use of ADCs for cancer therapy has achieved considerable success in recent years after the introduction of four clinically approved ADCs such as Brentuximab vedotin,, Trastuzumab emtansine –, Inotuzumab ozogamicin and Gemtuzumab ozogamicin, used for the treatment of patients with lymphoma (HL and ALL), HER2-positive, CD22-positive AML and CD33-positive ALL cancers, respectively. Likewise, a great deal of effort has also been made by the pharmaceutical companies to overcome the technological barriers associated with ADCs,, whereby there are 160 ADCs undergoing preclinical trials and 70 more under various stages of clinical evaluation (Table 1).

Clinical efficacy of the ADCs arises following accurate selection of four parameters including tumor targeting, antibody, cytotoxic payload, and method of antibody linkage to the payload. The precise selection of each parameter can be achieved through the knowledge gained from the previous studies and established ADCs, and is discussed here.

Tumor markers in ADCs

The important aspects of tumor markers in ADCs are demonstrated in figure 2. An antigen with expression pattern slightly greater in tumor cells compared to healthy cells is sufficient to induce ADC activity. However, like other targeted drug delivery systems, the number of cell surface tumor markers can be a key determinant of ADC activity. The targets for ADC do not necessarily intervene in cell growth. ADCs tumor-suppressive function is mainly mediated through tumor marker potency for ADC internalization compared to the inhibition by blocking the cell growth,–. However, target biological roles such as those involved in cell division pathway (e.g. CD30 and CD70 tumor necrosis factor signaling) can be considered as an advantage for ADC efficacy. Accordingly, the currently employed targets and their biological roles are listed in table 1.

For instance, glembatumumab vedotin is an ADC against an extracellular domain of non-metastatic B melanoma-associated glycoprotein (GPNMB) that is aberrantly expressed in various carcinoma including hepatocellular, melanoma, gliomas, and two specific breast cancer types, Basal-Like Breast Cancer (BLBC) and Triple Negative Breast Cancer (TNBC). The GPNMB do not represent a high relative level of expression in all aforesaid carcinoma. One important property that may make GPNMB a potential therapeutic target for ADCs, originates from its biological role in MAPK/ERK pathway, as GPNMB expression can be upregulated by MAPK/ERK inhibitors.

From the structure standpoint, a relevant antigenic determinant on cell surface membranes, termed Extracellular Domain (ECD), is required as an immunizing agent for antibody generation. However, the potential of ECD to be shed into the circulation must be considered. The shed ECDs can potentially bind to ADC and consequently reduce the targeted delivery into the tumor cells.

A further concern in the selection of the target for ADC is related to the homogeneity or heterogeneity expression of the tumor marker on the tumor cell surface. Homogenous expression of the tumor targets has been demonstrated to be more in favor of ADC targeting than those expressed heterogeneously. However, heterogeneous antigen expression can particularly be beneficial for those ADCs that possess bystander killing activity –. Bystander killing activity is referred to the potency of therapeutics delivery system in killing neighboring cells independently of targeted therapy assignment. This effect can be raised through reactive oxygen species or some cytotoxic metabolites that may be excreted from the tumor-targeted cells –. As a result, recycling capability of a tumor marker would enhance bystander killing activity as it may promote leakage of ADC and metabolites to the neighboring cells. However, according to the reports, an extra recycling property is not desirable as in further Bystander activity (Ba), the greater side effects are predicted,.

The promising future of the ADCs supports extensive studies to look for a potent ADC target with a wide range of expression, from earliest cell recognizable lineage to maturation. This represents an exquisitely selective target that covers all types of malignancies. CD19 is a good example of such target that is highly expressed in B-cell and the vast majority of Non-Hodgkin lymphomas (NHLs), and B-cell Acute Lymphoid Leukemia (B-ALL) (99%),–. As shown in table 1, CD19 has been marked as a target to produce ADCs, including SAR3419,,, SGN-CD19A, MDX-1206, and ADCT-402.

Antibodies in ADCs

Antibody component in ADCs undertakes both roles including being a carrier and targeting agent. The main aspects of the antibody in ADCs are demonstrated in figure 3. High specificity of targeting and minimal immunogenicity are the main characteristics for Ab component in ADCs. These prevent antibody cross reactions to other antigens, avoiding both toxicity and removal/elimination of the ADC before reaching to the tumor. The high affinity of the Ab for efficient uptake into target cells is another important factor in ADC design,–. To the best of our knowledge, there is no substantial report about optimal or even minimum required binding affinity (Kd) of antibody component. In figure 4, a binding affinity less than 10 nM (Kd<10 nM) is commonly needed for the Ab component and accordingly for an effective ADC, based on frequency distribution histogram. The affinity of the antibody to its immunogen can affect the property of antibody which is termed as receptor-mediated antibody internalization. Receptor-mediated antibody internalization is a key mechanism underlying antibody endocytosis that is induced through antibody binding to its specific antigen. It has been reported that, alternative antibodies against the same immunogen can exhibit different rates of internalization. Rapid internalization can raise both ADC efficacy and safety simultaneously, since it reduces the opportunity of the ADC for off-target release,.

In addition to rapid internalization as a prerequisite for an antibody, the route by which antibody is internalized should be also considered, because it can potentially influence ADC processing. For instance, Clathrin-coated Pit-mediated receptor internalization (caveolae pathway), at least in some cases, has been reported to traffic ADC to the cells. In caveolae pathway, ADC is directed to the Golgi or endoplasmic reticulum (Non-proteolytic compartments) instead of endosomes or lysosomes (Proteolytic compartment of the cells). ADC’s traffic to the non-proteolytic compartments may impede its proteolytic process to release effective metabolites. Antibody capability to induce receptor mediated internalization is somewhat a mandatory requirement in design of new generation of ADCs. Antibody with low internalization rate has no desired therapeutics index even for the tumors expressing high levels of surface antigen. To compensate inefficient internalizing of ADC, a much more potent drug and high stable linkage chemistry (linkage between the antibody and drug moiety) are required that would be discussed in next sections.

Optimal pharmacokinetic (PK) properties including longer half-life is another aspect of the antibody component in ADC design,,. It has been reported that Ab with longer half-life show high elimination and rapid clearance of the ADC in plasma. As shown in table 1, it is not compulsory for a mAb itself to represent therapeutic activity in the ADC. However, therapeutic activity of the mAb is a desirable property besides killing activity mediated by the cytotoxic payload,.

Antibody therapeutic activity is usually mediated via immune-mediated effector functions such as Antibody-Dependent Cellular Cytotoxicity (ADCC), Antibody-Dependent Cellular Phagocytosis (ADCP), Complement Dependent Cytotoxicity (CDC), and cytokine signaling modulation in terms of inhibition or induction (Table 1). Such therapeutic activities can be further employed to design ADCs with enhanced cell killing activity –,,–. According to the obtained data in table 1, isotype 1 immunoglobulin (IgG1) seems to be prone to induce immunotherapeutic activity.

In this regard, many attempts have been made to engineer mAbs with therapeutic activity. For instance, the Fc domain affinity of anti-CD19 targeting antibodies for the FcγRIII has been enhanced, either by Fc glycolengineering approaches, e.g. MEDI-55 and MDX-1342 or amino acid substitution, e.g. XmAb5574 and XmAb 5871 or MOR-208,. Such modification resulted in an increase of ADCC activity in antibody. To the best of our knowledge, the above engineered antibodies have not been used for designing ADCs yet. However, there are some reports of ADCs which have employed a combination/fusion of two engineered antibody fragments. Such fusion antibodies are termed as bispecific Antibody (bsAb), while ADCs designed from the bsAbs were named bispecific ADC (bsADC). Blinatumomab and AFM11 are typical bispecific antibodies, two fusions of anti-CD19 scFv and anti-CD3 scFv, which were engineered to enhance CD19-positive cells killing activity through induction of T or NK cytotoxic immune effector cells,. A derivative of blinatumomab has been also constructed to induce the controlled T cell activation, named ZW38. The ZW38 was conjugated to a microtubule cytotoxic agent for the preparation of a novel class of bsADC capable of mediating T cell cytotoxicity. Another bsADC, B10v5x225-H-vc-MMAE (Monomethyl auristatin EMMAE), has been recently developed to simultaneously target EGFR and c-MET which are two tyrosine kinases receptors correlated with tumor growth and metastasis,. B10v5x225-H-vc-MMAE contains a bsAb from fusion of anti c-MET Fab fragment and anti-EGFR scFv that was engineered to represent low affinity to EGFR which is a ubiquitous tissue antigen. The side effect of B10v5x225-H-vc-MMAE can be avoided to some extent due to attenuated affinity toward EGFR receptors in healthy cells. Bridging a rapidly internalizing protein with a tumor specific marker is also another recent method to construct bsAb, e.g., anti HER2 crosslink to prolactin cytoplasmic domain receptor with the ability to improve internalization and cell killing activity of the bsADC.

Cytotoxic payloads in ADCs

Briefly, cytotoxic payloads for new generation of ADCs should meet many of the criteria as outlined in figure 5. Antibody component in ADCs is incapable of carrying a large number of cytotoxic payload due to its structure. Therefore, the cytotoxic payload in the new generation of ADCs must be highly super-toxic to eradicate majority of the tumor cells even with minimal payload delivery. The rate of mAb uptake by tumor cells is approximately less than 0.003–0.08% of injected dose per gram in a tumor,. Furthermore, low expression and poor internalizing activity of the most tumor-associated antigens can cause negligible ADC delivery to the tumor target cells. Hence, ADCs equipped with highly super-cytotoxic payload are imperative, because they must show therapeutic effect while having limited release. According to the reports, a highly cytotoxic agent should exhibit an IC50 of about 10 nM or less obtained from an examination with KB cells upon a 24-hr exposure time,,,. A highly super cytotoxic payload can be originated from plant, animal or microorganisms; in this regard, the most important issue can be the finding of cytotoxic payloads with negligible immunogenic potential in the body. In new generation of ADCs, such cytotoxic payloads are likely to be chemical anti-cancer drugs since experimental evidence confirmed that they are less immunogenic than glycol/peptide cytotoxic agents when circulating in the blood. Some anticancer drugs such as doxorubicin (DOX), mitoxantrone, and etoposide are impaired under hypoxic condition; a condition appeared in solid cancer cell population,. Hence, needless to say, those drugs may not be considered as cytotoxic payloads.

Taking a look at current cytotoxic drugs (Table 1) shows that they generally affect DNA synthesis or cell division to block cell proliferation (mitosis),. Monomethyl auristatin derivatives which bind to tubulin and are able to inhibit microtubule assembly/polymerization (IC50=10–500 pM) are the most commonly used cytotoxic drugs in ADC design with approximately 50% share of the field (Table 1). Maytansinoids derivatives (∼30%), pyrrolobenzodiaze-pine (∼7%), camptothecin analogs (∼6%), n-acetyl-γ-calicheamicin (4%), duocarmycin (DUO) (∼3%) and doxorubicin (∼1%) are the other abundant cytotoxic payloads (Table 1). The above cytotoxic compounds are 100 to10000 folds more potent in vitro than typical chemotherapeutic agents and are chosen based on their different actions on cancer and noncancerous cells. DNA modulators have significant effects on malignant cells as they are divided more rapidly than normal cells.

Furthermore, a cytotoxic agent of the ADC is better to be studied in an in vitro condition to determine whether it is a substrate, inhibitor or inducer of metabolizing enzymes (e.g., cytochrome P-450 isozymes (CYPs), and some transporter enzymes like P-glycoprotein). Such studies help to elucidate the in vivo factors that may be contributed to the elimination/enhancement of the cytotoxic agent,,. New studies to introduce new payloads focused on agents against Tumor-Initiating Cells (TICs),. Such payloads assist to widen the target area and to circumvent potential resistance of cancer cells. Pyrrolobenzodiazepines (PBDs), derivatives of naturally occurring tricyclic antibiotics, duocarmycins, anthracyclines, α-amanitin (a bicyclic octapeptide from the fungus Amanita), and topoisomerase inhibitors including SN-38 are categorized as TIC payloads,.

Rovalpituzumab tesirine is one example of ADC with PBD as a payload (Table 1), that has been reported to have a potency to eliminate pulmonary neuroendocrine TICs at subpicomolar level in vivo.

The cytotoxic payload should be also stable during preparation or storage and circulation in the blood. Cytotoxic payloads that are not fully stable can potentially be converted to undesirable drug forms during conjugation or storage. Solubility of the cytotoxic agent in aqueous solution is another important criterion in ADC design. Antibody is considered a protein and its conjugation to the cytotoxic agent must be performed in aqueous solutions with minimal organic cosolvents,. Extreme hydrophobicity of payload can potentially change antibodies biological properties, resulting in hydrophobic aggregation of the antibody either during conjugation process or storage. The hydrophilicity of cytotoxic payloads will affect cell membrane permeability of parent ADC or its metabolites which may also be beneficial in term of bystander activity,,,. However, the ability of cytotoxic payloads to form hydrophobic metabolite after intercellular cleavage of ADC is preferable since the metabolites with more hydrophobic group show better blood clearance and safety. According to the reports, about 95–99% of ADC molecules are metabolized before binding to tumor cells. This may raise safety concern as it can enhance the potential cytotoxic side effects of ADC. Thereby, the use of cytotoxic payloads with well-characterized metabolite profiles can be an advantage to enhance ADC safety in particular,,–.

Cytotoxic payload should present a dominant functional group suitable for linkage to the antibody component of ADC. If a dominant functional group does not exist on the cytotoxic agent, at least, it should be amenable to modification, in which a desired substituent is introduced on appropriate sites.

The copy number and heterogeneity of antigen expression are the other important issues that must be considered in the selection of cytotoxic agent,. More expression of target antigen may be a reason to apply a cytotoxic agent with low potency. Typically, payloads that promote the bystander effect in cancer cells are more desirable to design ADCs directed for the antigens expressed heterogeneously.

The ability to choose specified cytotoxic payloads with mechanism of action compatible with standard of care has been reported to facilitate clinical success of the ADCs in biopharmaceutical market. For instance, microtubule disrupting payloads are commonly chemotherapeutic drugs that are used for the treatment of cancers, including breast, ovarian and prostate cancer, (Table 1). Both availability in the market and reasonable cost can be alternative rationale for choosing a cytotoxic payload in ADC design.

Linking cytotoxic payloads to antibodies in ADCs

One of the dynamic research fields in ADC design is the study of the methods that are correlated with antibody conjugation to cytotoxic payloads, as it has a great role on balancing between ADC therapeutic efficacy and toxicity,,. The key concerns in linkage chemistry are demonstrated in figure 6. Conjugation site on antibody component, a well-defined Drug to Antibody Ratio (DAR), homogeneity and linkage stability are the important parameters that need to be considered in conjugation.

In general, interchain disulfide bridges and surface-exposed lysines are the most currently used residues on the antibody for conjugation to cytotoxic payloads, respectively (>50 vs. >30%) (Table 1). Hydroxyl groups on carbohydrate structures are the other residues in antibodies that have been rarely used as conjugation sites for ADC (The schematic linkage in figure 6 is an example of this strategy),.

Theoretically, the linkage of cytotoxic payloads to the surface-exposed lysine of mAb occurs after reduction of ∼40 lysine residues on both heavy and light chain of mAb and it results in 0–8 cytotoxic payload linkages per antibody and heterogeneity with about one million different ADC species,. Cysteine conjugation occurs after reduction of four interchain disulfide bonds and results in eight exposed sulfhydryl groups. Linking drugs per antibody can differ from zero to 8 molecules, generating a heterogeneous population of ADC (Greater than one hundred different ADC species).

Due to low stability and safety properties of the pharmaceutical products with heterogeneous contents, they are complex to be accurately predicted in terms of efficacy or therapeutic window,. Therefore, improvement of conjugation methods to achieve homogeneous ADC is very crucial.

In this case, it is possible to reduce just two of four interchain mAb’s disulfide bonds of cysteine residues through carefully mild reduction conditions, as interchain disulfide bridges are more prone to reduction than intrachain disulfide bridges,,. However, such mild reduction is not easily possible in practice and a diverse number of cysteines may be reduced (0–4), resulting in a heterogeneous mixture of ADC,. Hence, the production of homogeneous ADCs through payload conjugation with native residues can be laborious. To overcome this limitation, many site-specific conjugation approaches have been developed, in which a known number of cytotoxic payloads are constantly conjugated to defined sites on mAbs. Some of the approaches are explained below: A conjugation through engineered cysteine residues that neither damages antibody fab region nor interferes with Fc-mediated effector functions, called THIOMAB technology,. In THIOMAB technology, the heavy chain alanine 114 is substituted with two or more reactive cysteine residues at a predefined site for conjugation with cytotoxic payload. Anti-TENB2 ADC is an example that is prepared by THIOMAB technology and is currently in phase I trial (Table 1).Re-engineering of mAb is able to incorporate with unnatural amino acids, e.g. selenocysteine, acetyl-phenylalanine, and para-azidomethyl-l-phenylalanine.Site-specific enzyme-mediated conjugation to genetically engineered antibody is as follows: Incorporating a thiolated sugar analogue, 6-thiofucose, to the antibody carbohydrate that introduces new chemically active thiol groups using fucosyltransferase VIII,Providing a ketone reactive group on antibody glycosylation site by glycotransferases,Introducing an aldehyde reactive group on the antibody using sialyltransferase or formylglycine-generating enzyme,Genetically introducing specific glutamine tags to antibody whereby payloads with a primary amine group can be linked to the γ-carbonyl amide group of glutamine tags. Such reaction is catalyzed by a microbial transglutaminase which is capable of recognizing glutamines tags from naturally glutamines residues,–,Providing LPXTG tagged antibodies (A penta-peptide as a substrate for transpeptidation reaction) as specific linkage sites for the oligo-glycine-containing payloads, which are mediated by Staphylococcus aureus Sortase A enzyme,Conjugation of phosphopantetheine-linked payloads to the serine residues of the peptide-tagged antibodies via phosphopantetheinyl transferases catalysis,Chemoenzymatic site direct conjugation, e.g., providing two azide groups at asparagine 297 (Asn-297) residue in antibody constant region (Fc) is linked with cytotoxic payloads using copper-mediated click reaction. The azide functional groups are formed in a selective hydrolysis reaction that is mediated by an Endo-beta-N-acetylglucosaminidase (EndoS) chemoenzyme.

A conjugation through engineered cysteine residues that neither damages antibody fab region nor interferes with Fc-mediated effector functions, called THIOMAB technology,. In THIOMAB technology, the heavy chain alanine 114 is substituted with two or more reactive cysteine residues at a predefined site for conjugation with cytotoxic payload. Anti-TENB2 ADC is an example that is prepared by THIOMAB technology and is currently in phase I trial (Table 1).

Re-engineering of mAb is able to incorporate with unnatural amino acids, e.g. selenocysteine, acetyl-phenylalanine, and para-azidomethyl-l-phenylalanine.

Site-specific enzyme-mediated conjugation to genetically engineered antibody is as follows: Incorporating a thiolated sugar analogue, 6-thiofucose, to the antibody carbohydrate that introduces new chemically active thiol groups using fucosyltransferase VIII,Providing a ketone reactive group on antibody glycosylation site by glycotransferases,Introducing an aldehyde reactive group on the antibody using sialyltransferase or formylglycine-generating enzyme,Genetically introducing specific glutamine tags to antibody whereby payloads with a primary amine group can be linked to the γ-carbonyl amide group of glutamine tags. Such reaction is catalyzed by a microbial transglutaminase which is capable of recognizing glutamines tags from naturally glutamines residues,–,Providing LPXTG tagged antibodies (A penta-peptide as a substrate for transpeptidation reaction) as specific linkage sites for the oligo-glycine-containing payloads, which are mediated by Staphylococcus aureus Sortase A enzyme,Conjugation of phosphopantetheine-linked payloads to the serine residues of the peptide-tagged antibodies via phosphopantetheinyl transferases catalysis,

Incorporating a thiolated sugar analogue, 6-thiofucose, to the antibody carbohydrate that introduces new chemically active thiol groups using fucosyltransferase VIII,

Providing a ketone reactive group on antibody glycosylation site by glycotransferases,

Introducing an aldehyde reactive group on the antibody using sialyltransferase or formylglycine-generating enzyme,

Genetically introducing specific glutamine tags to antibody whereby payloads with a primary amine group can be linked to the γ-carbonyl amide group of glutamine tags. Such reaction is catalyzed by a microbial transglutaminase which is capable of recognizing glutamines tags from naturally glutamines residues,–,

Providing LPXTG tagged antibodies (A penta-peptide as a substrate for transpeptidation reaction) as specific linkage sites for the oligo-glycine-containing payloads, which are mediated by Staphylococcus aureus Sortase A enzyme,

Conjugation of phosphopantetheine-linked payloads to the serine residues of the peptide-tagged antibodies via phosphopantetheinyl transferases catalysis,

Chemoenzymatic site direct conjugation, e.g., providing two azide groups at asparagine 297 (Asn-297) residue in antibody constant region (Fc) is linked with cytotoxic payloads using copper-mediated click reaction. The azide functional groups are formed in a selective hydrolysis reaction that is mediated by an Endo-beta-N-acetylglucosaminidase (EndoS) chemoenzyme.

ADC as a potential targeted delivery system must be passed through all hurdles, including blood circulation, antigen binding, internalization, payload release, and eventual payload action. An unstable linkage can lead to premature release of the payload, before reaching the site of action. Therefore, reasonable chemical stability must be considered in the design of chemical linkage between cytotoxic payload and antibody.

Although a direct linkage between cytotoxic and antibody components has generally shown more stability in circulation,, conjugation reactions are mostly created with linkers in comparison with direct linkage between cytotoxic and antibody component (Table 1). The choice of proper linkers has been discussed in the related publications devoted to the progress of ADCs,,,,. As shown in table 1, about 50% of the ADCs are using Valine-Citrulline peptidyl (VC) linker. N-succinimidyl 4-(2-pyridyldithio) butyrate (SPDB) (18%), acid-labile hydrazine (10%), maleimidomethyl cyclohexane-1-carboxylate (MCC), maleimidocaproyl (MC) (10%), N-succinimidyl 4-(2-pyridyldithio pentanoate (SPP) and carbonate (3%) linkers are other employed linkers.

Limited drug-linker designs for more than 70 current ADC clinical trials (Table 1) are a dilemma regarding linkage chemistry that may restrict simultaneous development of ADCs against both hematological and solid tumors. Generally, the properties of linkers can be altered by the cytotoxic payload release mechanism. Cytotoxic payload in ADC technology must be released into the cell to exert its therapeutic activity, thus ADC linkers should be chosen based on their stability to keep ADC intact during circulation and capable of cleaving inside the targeted cell,. Linker stability is defined based on lack/low level of cleaving agents (e.g., protease or reductive agents) in the bloodstream compared to the cytoplasm.

The current linkers used in ADCs are also broadly classified as cleavable and noncleavable linkers based on where they are cleaved into the cytoplasm. Cleavable linkers are those containing a conditional cleavage sites sensitive to be cleaved immediately after ADC internalization, such as VC, SPDB, SPP, and hydrazine which can be triggered through protease reactions, glutathione reduction, and acidic pH, respectively,. Noncleavable linkers are stable from early to late endosome transition and their cytotoxic partner is just released by degradation of antibody in lysosomes, e.g. MCC and MC linkers that link Ab to the payload via thioether linkage.

Characteristics of ADC target such as copy number, internalization rate and level of homogeneity should be considered in conjugation method and linker selection. For instance, ADC with disulfide-linkage has been shown to have more cytotoxic activity than the same ADC with thioether linkage when they were directed to the tumor cell lines expressing a low copy number of targeted antigen.

Cleavable linkers may increase the possibility of bystander effect. Hence, it is logical to use cleavable linkers in designing ADCs directed for the antigen that is heterogeneously expressed in tumors.

In vivo adverse effects of ADCs are influenced by the use of cleavable or noncleavable linkers. As in the case of tubulin inhibitor payloads, which is linked through cleavable linkers to the antibody component, e.g. SPDB-DM4 (Ravtansine-DM4), or VC-MMAE, peripheral neuropathy can be frequently observed, whereas noncleavable linkers often trigger hematological toxicity, possibly due to an increased dose and interactions with Fcγ receptors on hematopoietic cells.

The type of linker plays an important role in ADC catabolite products with regard to processing into targeted cells or metabolizing by clearance mechanisms. The type of ADC catabolites may influence some ADC features such as IC50, Maximum Tolerated Dose (MTD),, and kill Multidrug Resistance (MDR) expressing cells,.

Conclusion

ADC is considered exciting and promising antibody-based therapeutics to improve cancer therapy. Growth in the number of registered ADCs in clinical trials (Table 1) represents the pharmaceutical industry interest in investment for research and development in the field, as it has been stated by others,.

The design of an ADC might seem to be not very complex, while several issues must be taken into consideration to complete ADC’s potential as a therapeutic agent for cancer. This might be the main reason for the condition that small number of ADCs have reached the market (Table 1). The major issues associated with the development of ADCs seem to be originated from the factors that interfere with ADCs efficacy and off-target cytotoxicity. The precise selection of all four parameters, i.e. tumor marker, antibody, cytotoxic payload, and linkage strategy would be required to prepare a successful ADC.

With regard to ADC tumor markers, they do not have to be involved in tumor growth,,,. Therefore, ADC can present therapeutic application in a broad range of tumors. However, an ADC tumor marker should meet at least three criteria of considerable expression level in tumor cells vs. normal cells, presenting cell surface immunogen, and being capable of performing ADC internalization.

High specificity, adequate affinity, and receptor-mediated internalization are the major aspects of antibody choice. Efforts to optimize antibody component would be a great idea to translate into improved ADCs. In fact, some major ADCs’ weaknesses including, low efficiency, low internalization, off-target effect due to the target expression in normal tissues, and heterogeneity expression of the target in the tumors can be overcome via antibody improvement. Antibody engineering technology for production of alternative bsAbs to design more efficient ADCs (bsADCs) has been proven in several preclinical models,,. The rationale behind this technology is the fact that the aforesaid ADC’s weaknesses can be solved through ADC designs (bsADCs) operating from improved antibody (bsAb) in terms of affinity, specificity, internalization activity, by enhancing the therapeutic activity or decreasing ADC’s side effects.

Another main concern in the development of ADCs is related to the study of finding cytotoxic payloads that are potent enough with confined DAR (Up to 7 drugs per antibody) to exert therapeutic activity. Having reasonable aqueous solubility, non-immunogenic, as well as stability in storage and bloodstream is a common criterion for choosing cytotoxic payloads.

In contrast, the introduction of innovative methods to modify ADCs cytotoxic payloads with versatile functional groups (e.g. thiol, amine groups) is the other interesting subject, as it eases the conjugation process. One further challenge of ADCs is associated with the limitation of linkage and conjugation chemistry to link an optimized number of the payloads to the antibody in predefined location homogeneously.

Interdisciplinary and multidisciplinary works and related studies such as recombinant DNA technology, bioconjugation, and chemistry are the hopeful strategies to get the purpose of achievement in site-specific conjugation and homogeneous ADCs,,–,,.

Based on promising reports from research to synthesize homogeneous ADCs, it is likely that the first ADC products constructed using site-specific conjugation will be made for cancer therapy that may hold the promise about the future use of ADCs.

Taken together, despite challenges in ADC design, the future of ADCs seems to be much promising as more clinical trials and basic researches conducted on existing ADCs would pave the way to tackle issues regarding tumor marker, antibody, cytotoxic payload, and linkage strategy.

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  12. 12.

    García-Alonso S Ocaña A Pandiella A Resistance to antibody-drug conjugates. Cancer Res 2018;78(9):2159–2165.

    Not in our library10.1158/0008-5472.can-17-3671

  13. 13.

    Jen EY Ko CW Lee JE Del Valle PL Aydanian A Jewell C FDA Approval: Gemtuzumab ozogamicin for the treatment of adults with newly-diagnosed CD33-positive acute myeloid leukemia. Clin Cancer Res 2018. [Epub ahead of print].

    Not in our library10.1158/1078-0432.ccr-17-3179

  14. 14.

    Beck A Reichert JM Antibody-drug conjugates: present and future. MAbs 2014;6(1):15–17.

    Not in our library10.4161/mabs.27436

  15. 15.

    Webb S Pharma interest surges in antibody drug conjugates. Nat Biotechnol 2011;29(4):297–298.

    Not in our library10.1038/nbt0411-297

  16. 16.

    Firth D Bell L Squires M Estdale S McKee C A rapid approach for characterization of thiol-conjugated antibody-drug conjugates and calculation of drug–antibody ratio by liquid chromatography mass spectrometry. Anal Biochem 2015;485:34–42.

    Not in our library10.1016/j.ab.2015.06.001

  17. 17.

    Ab O Whiteman KR Bartle LM Sun X Singh R Tavares D IMGN853, a folate receptor alpha (FRα)-targeting antibody-drug conjugate, exhibits potent targeted anti-tumor activity against FRα-expressing tumors. Mol Cancer Ther 2015;14(7):1605–1613.

    Not in our library10.1158/1535-7163.mct-14-1095

  18. 18.

    Casi G Neri D Antibody-drug conjugates: basic concepts, examples and future perspectives. J Control Release 2012;161(2):422–428.

    Not in our library10.1016/j.jconrel.2012.01.026

  19. 19.

    Leipold D Mallet WG Case Study: An antibody-drug conjugate targeting MUC16 for ovarian cancer. In: Phillips GL, editor. Antibody-drug conjugates and immunotoxins. New York: Human Press; 2013 p. 221–239.

    Not in our library

  20. 20.

    Ritchie M Tchistiakova L Scott N Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. MAbs 2013;5(1):13–21.

    Not in our library10.4161/mabs.22854

  21. 21.

    Onaga M Ido A Hasuike S Uto H Moriuchi A Nagata K Osteoactivin expressed during cirrhosis development in rats fed a choline-deficient, l-amino acid defined diet, accelerates motility of hepatoma cells. J Hepatol 2003;39(5):779–785.

    Not in our library10.1016/s0168-8278(03)00361-1

  22. 22.

    Williams MD Esmaeli B Soheili A Simantov R Gombos DS Bedikian AY GPNMB expression in uveal melanoma: a potential for targeted therapy. Melanoma Res 2010;20(3):184–190.

    Not in our library10.1097/cmr.0b013e3283364a08

  23. 23.

    Kuan CT Wakiya K Dowell JM Herndon JE 2nd Reardon DA Graner MW Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin Cancer Res 2006;12(7 Pt 1):1970–1982.

    Not in our library10.1158/1078-0432.ccr-05-2797

  24. 24.

    Maric G Rose AA Annis MG Siegel PM Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer. Onco Targets Ther 2013;6:839–852.

    Not in our library10.2147/ott.s44906

  25. 25.

    Qian X Mills E Torgov M LaRochelle WJ Jeffers M Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate. Mol Oncol 2008;2 (1):81–93.

    Not in our library10.1016/j.molonc.2008.02.002

  26. 26.

    Kovtun YV Audette CA Ye Y Xie H Ruberti MF Phinney SJ Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res 2006;66(6): 3214–3221.

    Not in our library10.1158/0008-5472.can-05-3973

  27. 27.
    Antibody-drug conjugates—an emerging class of cancer treatment · 2016
    No notice
  28. 28.

    Golfier S Kopitz C Kahnert A Heisler I Schatz CA Stelte-Ludwig B Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther 2014;13(6):1537–1548.

    Not in our library10.1158/1535-7163.mct-13-0926

  29. 29.

    Shantha Kumara HM Grieco MJ Caballero OL Su T Ahmed A Ritter E MAGE-A3 is highly expressed in a subset of colorectal cancer patients. Cancer Immun 2012;12:16.

    Not in our library

  30. 30.

    Panowski S Bhakta S Raab H Polakis P Junutula JR Site-specific antibody drug conjugates for cancer therapy. MAbs 2014;6(1):34–45.

    Not in our library10.4161/mabs.27022

  31. 31.

    Sievers EL Senter PD Antibody-drug conjugates in cancer therapy. Annu Rev Med 2013;64:15–29.

    Not in our library10.1146/annurev-med-050311-201823

  32. 32.

    Gerber HP Kung-Sutherland M Stone I Morris-Tilden C Miyamoto J McCormick R Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and-resistant lymphomas. Blood 2009;113(18):4352–4361.

    Not in our library10.1182/blood-2008-09-179143

  33. 33.

    Kahl B Hamadani M Caimi PF Reid EG Havenith K He S First clinical results of ADCT-402, a novel pyrrolobenzodiazepine-based antibody drug conjugate (ADC), in relapsed/refractory B-cell linage NHL. Hematol Oncol 2017;35(S2):49–51.28591412

    Not in our library

  34. 34.

    Lazar AC Wang L Blättler WA Amphlett G Lambert JM Zhang W Analysis of the composition of immunoconjugates using size-exclusion chromatography coupled to mass spectrometry. Rapid Commun Mass Spectrom 2005;19(13):1806–1814.

    Not in our library10.1002/rcm.1987

  35. 35.

    Naddafi F Davami F Anti-CD19 monoclonal antibodies: a new approach to lymphoma therapy. Int J Mol Cell Med 2015;4(3):143–151.

    Not in our library

  36. 36.

    Rao C Pan C Vangipuram R Huber M Vemuri K Stevens A Efficacy and toxicity of an anti-CD19 antibody drug conjugate. American Association for Cancer Research Meeting; 2010; Abstr 2452.

    Not in our library

  37. 37.

    Black J Menderes G Bellone S Schwab CL Bonazzoli E Ferrari F SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows antitumor activity in uterine serous carcinoma with HER2/Neu expression. Mol Cancer Ther 2016;15(8):1900–1909.

    Not in our library10.1158/1535-7163.mct-16-0163

  38. 38.

    Elgersma RC Coumans RGE Huijbregts T Menge WMPB Joosten JAF Spijker HJ Design, synthesis, and evaluation of linker-duocarmycin payloads: toward selection of HER2-Targeting antibody-drug conjugate SYD985. Mol Pharm 2015;12(6):1813–1835.

    Not in our library10.1021/mp500781a

  39. 39.

    Menderes G Bonazzoli E Bellone S Black J Altwerger G Masserdotti A SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression. Gynecol Oncol 2017; 46(1):179–186.

    Not in our library10.1016/j.ygyno.2017.04.023

  40. 40.

    Yurkovetskiy A Gumerov D Ter-Ovanesyan E Conlon P Devit M Bu C, editors. Non-clinical pharmacokinetics of XMT-1522, a HER2 targeting auristatin-based antibody drug conjugate. American Association for Cancer Research Annual Meeting; 2017 Apr 1–5; Washington, DC Philadelphia (PA): AACR; Cancer Res July 2017.

    Not in our library

  41. 41.

    Humphreys RC Kirtely J Hewit A Biroc S Knudsen N Skidmore L, et al, editors. Site specific conjugation of ARX-788, an antibody drug conjugate (ADC) targeting HER2, generates a potent and stable targeted therapeutic for multiple cancers. 106th Annual Meeting of the American Association for Cancer Research; 2015 April 18–22; Philadelphia, PA Philadelphia (PA):AACR.

    Not in our library

  42. 42.

    Zammarchi F Chivers S Williams DG Adams L Mellinas-Gomez M Tyrer P ADCT-502, a novel pyrrolobenzodiazepine (PBD)-based antibody–drug conjugate (ADC) targeting low HER2-expressing solid cancers. Eur J Cancer 2016;69:S28.

    Not in our library

  43. 43.

    Gan HK Papadopoulos KP Fichtel L Lassman AB Merrell R Van Den Bent MJ Phase I study of ABT-414 mono- or combination therapy with temozolomide (TMZ) in recurrent glioblastoma (GBM). J Clin Oncol 2015,33(suppl;abstr 2016).

    Not in our library

  44. 44.

    Hamblett KJ Kozlosky CJ Siu S Chang WS Liu H Foltz IN AMG 595, an anti-EGFRvIII antibody-drug conjugate, induces potent antitumor activity against EGFRvIII-Expressing glioblastoma. Mol Cancer Ther 2015;14(7):1614–1624.

    Not in our library10.1158/1535-7163.mct-14-1078

  45. 45.

    Chittenden TD Setiady YY Park PU Ponte JF Dong L Skaletskaya A IMGN289, an EGFR-targeting antibody-maytansinoid conjugate with potent activity against non-small cell lung cancer (NSCLC) regardless of dependency on EGFR pathway. Proceedings: AACR 104th Annual Meeting 2013; Apr 6–10, 2013; Washington, DC.

    Not in our library

  46. 46.

    Calvo E Cleary JM Moreno V Preliminary results from a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to express EGFR. J Clin Oncol 2017;35:2510.

    Not in our library

  47. 47.

    Tannir NM Forero-Torres A Ramchandren R Pal SK Ansell SM Infante JR Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Invest New Drugs 2014;32(6): 1246–1257.

    Not in our library10.1007/s10637-014-0151-0

  48. 48.

    Owonikoko TK Hussain A Stadler WM Smith DC Sznol M Molina AM A phase 1 multicenter openlabel dose-escalation study of BMS-936561 (MDX-1203) in clear cell renal cell carcinoma (ccRCC) and Bcell non Hodgkin lymphoma (B-NHL). American Society of Clinical Oncology meeting abstracts 32;2014: 2558.

    Not in our library

  49. 49.

    Sandall SL McCormick R Miyamoto J Biechele T Law C-L Lewis TS SGN-CD70A, a pyrrolobenzodiazepine (PBD) dimer linked ADC, mediates DNA damage pathway activation and G2 cell cycle arrest leading to cell death. Proceedings: AACR 106th Annual Meeting 2015; April 18–22, 2015; Philadelphia, PA.

    Not in our library

  50. 50.

    U.S. National Library of Medicine [Internet] Bethesda (MD): U.S. National Library of Medicine 2000 Feb -. AMG 172 First in Human Study in Patients with Kidney Cancer; 2016 3 25 [cited 2018 June 08]; [about 4 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT01497821.

    Not in our library

  51. 51.

    Sievers E Appelbaum FR Spielberger R Forman S Flowers D Smith F Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 1999;93(11):3678–3684.

    Not in our library

  52. 52.

    Kung Sutherland MS Walter RB Jeffrey SC Burke PJ Yu C Kostner H SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 2013;122(8):1455–1463.

    Not in our library10.1182/blood-2013-03-491506

  53. 53.

    Lapusan S Vidriales MB Thomas X De Botton S Vekhoff A Tang R Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia. Invest New Drugs 2012;30(3):1121–1131.

    Not in our library10.1007/s10637-011-9670-0

  54. 54.

    Chari RV Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 2008;41(1):98–107.

    Not in our library10.1021/ar700108g

  55. 55.

    Hughes B Antibody-drug conjugates for cancer: poised to deliver? Nat Rev Drug Discov 2010;9(9):665–667.

    Not in our library10.1038/nrd3270

  56. 56.

    Rudnick SI Lou J Shaller CC Tang Y Klein-Szanto AJ Weiner LM Influence of affinity and antigen internalization on the uptake and penetration of Anti-HER2 antibodies in solid tumors. Cancer Res 2011;71 (6):2250–2259.

    Not in our library10.1158/0008-5472.can-10-2277

  57. 57.

    Bendell J Blumenschein G Zinner R Hong D Jones S Infante J First-in-human phase 1 dose escalation study of a novel anti-mesothelin antibody drug conjugate, BAY 94–9343. patients with advanced solid tumors, American Association of Cancer Research, Washington, DC.

    Not in our library

  58. 58.

    Zhao XY Subramanyam B Sarapa N Golfier S Dinter H Novel antibody therapeutics targeting mesothelin in solid tumors. Clin Cancer Drugs 2016;3(2):76–86.

    Not in our library10.2174/2212697x03666160218215744

  59. 59.

    Weekes CD Lamberts LE Borad MJ Voortman J McWilliams RR Diamond JR A phase I study of DMOT4039A, an antibody-drug conjugate (ADC) targeting mesothelin (MSLN), in patients (pts) with unresectable pancreatic (PC) or platinum-resistant ovarian cancer (OC). American Society of Clinical Oncology; 2014.

    Not in our library10.1158/1535-7163.mct-15-0693

  60. 60.

    Weekes CD Lamberts LE Borad MJ Voortman J McWilliams RR Diamond JR Phase I study of DMOT4039A, an antibody-drug conjugate targeting mesothelin, in patients with unresectable pancreatic or platinum-resistant ovarian cancer. Mol Cancer Ther 2016;15 (3):439–447.

    Not in our library10.1158/1535-7163.mct-15-0693

  61. 61.

    Advani A Coiffier B Czuczman MS Dreyling M Foran J Gine E Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study. J Clin Oncol 2010;28(12):2085–2093.

    Not in our library10.1200/jco.2009.25.1900

  62. 62.

    DiJoseph JF Armellino DC Boghaert ER Khandke K Dougher MM Sridharan L Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 2004;103(5):1807–1814.

    Not in our library10.1182/blood-2003-07-2466

  63. 63.

    Dotan E Cohen SJ Starodub AN Lieu CH Messersmith WA Simpson PS Phase I/II trial of labetuzumab govitecan (Anti-CEACAM5/SN-38 antibody-drug conjugate) in patients with refractory or relapsing metastatic colorectal cancer. J Clin Oncol 2017;35(29):3338–3346.

    Not in our library10.1200/jco.2017.73.9011

  64. 64.

    Dotan E Starodub A Berlin J Lieu CH Guarino MJ Marshall J A new anti-CEA-SN-38 antibody-drug conjugate (ADC), IMMU-130, is active in controlling metastatic colorectal cancer (mCRC) in patients (pts) refractory or relapsing after irinotecan-containing chemotherapies: Initial results of a phase I/II study. American Society of Clinical Oncology; 2015.

    Not in our library

  65. 65.

    Govindan SV Cardillo TM Rossi EA Trisal P McBride WJ Sharkey RM Improving the therapeutic index in cancer therapy by using antibody-drug conjugates designed with a moderately cytotoxic drug. Mol Pharm 2014;12(6):1836–1847.

    Not in our library10.1021/mp5006195

  66. 66.

    Gazzah A Stjepanovic N Ryu M Tabernero J Soria J Bedard P First-in-human phase I trial of the anti-CEACAM5 antibody-drug conjugate SAR408701 in patients with advanced solid tumors (NCT02187848). Europ J Cancer 2016;69:S14–S5.

    Not in our library

  67. 67.

    Bardia A Mayer IA Diamond JR Moroose RL Isakoff SJ Starodub AN Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 2017;35 (19):2141–2148.

    Not in our library10.1200/jco.2016.70.8297

  68. 68.
    Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC)* · 2015
    No notice
  69. 69.

    Heist RS Guarino MJ Masters G Purcell WT Starodub AN Horn L Therapy of advanced nonsmall-cell lung cancer with an SN-38-anti-trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol 2017;35(24):2790–2797.

    Not in our library10.1200/jco.2016.72.1894

  70. 70.

    Ocean AJ Starodub AN Bardia A Vahdat LT Isakoff SJ Guarino M Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics. Cancer 2017;123(19):3843–3854.

    Not in our library10.1002/cncr.30789

  71. 71.

    Starodub A Camidge DR Scheff RJ Thomas SS Guarino MJ Masters GA Trop-2 as a therapeutic target for the antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132), in patients (pts) with previously treated metastatic small-cell lung cancer (mSCLC). American Society of Clinical Oncology meeting Abstract. 2016;34(15 suppl):8559.

    Not in our library

  72. 72.

    Starodub AN Ocean AJ Shah MA Guarino MJ Picozzi VJ Vahdat LT First-in-human trial of a novel anti-Trop-2 antibody-SN-38 conjugate, sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res 2015;21(17):3870–3878.

    Not in our library10.1158/1078-0432.ccr-14-3321

  73. 73.

    Strop P Tran TT Dorywalska M Delaria K Dushin R Wong OK RN927C, a site-specific trop-2 antibody–drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther 2016;15(11):2698–2708.

    Not in our library10.1158/1535-7163.mct-16-0431

  74. 74.

    Petrylak DP Kantoff PW Mega AE Vogelzang NJ Stephenson J Fleming MT Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane. American Society of Clinical Oncology meeting Abstract. 2013;31(Suppl; Abstr 5018).

    Not in our library

  75. 75.

    Wang X Ma D Olson WC Heston WD In vitro and in vivo responses of advanced prostate tumors to PSMA ADC, an auristatin-conjugated antibody to prostate specific membrane antigen. Mol Cancer Ther 2011;10(9): 1728–1739.

    Not in our library10.1158/1535-7163.mct-11-0191

  76. 76.

    Henry MD Wen S Silva MD Chandra S Milton M Worland PJ A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer. Cancer Res 2004;64(21):7995–8001.

    Not in our library10.1158/0008-5472.can-04-1722

  77. 77.

    Lammerts van Bueren JJ Bleeker WK Bøgh HO Houtkamp M Schuurman J van de Winkel JG Effect of target dynamics on pharmacokinetics of a novel therapeutic antibody against the epidermal growth factor receptor: implications for the mechanisms of action. Cancer Res 2006;66(15):7630–7638.

    Not in our library10.1158/0008-5472.can-05-4010

  78. 78.

    Hicks SW Lai KC Gavrilescu LC Yi Y Sikka S Shah P The antitumor activity of IMGN529, a CD37-targeting antibody-drug conjugate, is potentiated by rituximab in non-Hodgkin lymphoma models. Neoplasia 2017;19(9):661–671.

    Not in our library10.1016/j.neo.2017.06.001

  79. 79.

    Stathis A Freedman AS Flinn IW Maddocks KJ Weitman S Berdeja JG A phase I study of IMGN529, an antibody-drug conjugate (ADC) targeting CD37, in adult patients with relapsed or refractory b-cell nonhodgkin’s lymphoma (NHL). Blood 2014;124(21):1760.

    Not in our library

  80. 80.

    Doñate F Yang P Morrison K Karki S Aviña H Lackey J Analysis of preclinical and clinical samples after treatment with a CD37 targeting antibody drug conjugate (AGS67E) support a high level of CD37 expression in NHL. Hematol Oncol 2017;35(S2):290–291.

    Not in our library

  81. 81.

    Sawas A Savage KJ Perez R Advani RH Butturini A Lackey J A phase 1 study of the anti-CD37 antibody-drug conjugate AGS67E in advanced lymphoid malignancies. Interim results. Blood 2015;126(23):3976.

    Not in our library

  82. 82.

    Kogawa T Yonemori K Naito Y Noguchi E Shimizu C Tamura K Phase 1/2, multicenter, nonrandomized, open-label, multiple-dose first-in-human study of U3–1402 (anti-HER3 antibody drug conjugate) in subjects with HER3-positive metastatic breast cancer. J Clin Oncol 2017;35:TPS1116.

    Not in our library

  83. 83.

    Saunders LR Bankovich AJ Anderson WC Aujay MA Bheddah S Black K A DLL3-targeted antibody drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 2015;7(302):302ra136.

    Not in our library10.1126/scitranslmed.aac9459

  84. 84.

    Ott P Pavlick A Johnson D Hart L Infante J Luke J A phase 2 study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma. Ann Oncol 2016;27(suppl 1147: 6p).26598541

    Not in our library

  85. 85.

    Rose AA Biondini M Curiel R Siegel PM Targeting GPNMB with glembatumumab vedotin: current developments and future opportunities for the treatment of cancer. Pharmacol Ther 2017;179:127–141.

    Not in our library10.1016/j.pharmthera.2017.05.010

  86. 86.

    Saleh M Bendell J Rose A Siegel P Hart L Sirpal S Correlation of GPNMB expression with outcome in breast cancer (BC) patients treated with the antibody–drug conjugate (ADC), CDX-011 (CR011-vcMMAE). J Clin Oncol 2010;28(15_suppl):1095.

    Not in our library

  87. 87.

    Yardley DA Melisko ME Forero A Daniel BR Montero AJ Guthrie TH METRIC: a randomized international study of the antibody-drug conjugate glembatumumab vedotin (GV or CDX-011) in patients (pts) with metastatic gpNMB-overexpressing triple negative breast cancer (TNBC). J Clin Oncol 2015;33(Suppl; abstr TPS-1110).

    Not in our library

  88. 88.

    Palanca-Wessels MC Czuczman M Salles G Assouline S Sehn LH Flinn I Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015;16(6):704–715.

    Not in our library10.1016/s1470-2045(15)70128-2

  89. 89.

    Almhanna K Wright D Mercade TM Van Laethem JL Gracian AC Guillen-Ponce C A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C. Invest New Drugs 2017;35(5):634–641.

    Not in our library10.1007/s10637-017-0473-9

  90. 90.

    Cruz Zambrano C Almhanna K Messersmith WA Rodon Ahnert J Ryan DP Faris JE MLN0264, an investigational antiguanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) malignancies: Phase I study. J Clin Oncol 2014;32(Suppl; abstr 3456).

    Not in our library

  91. 91.

    Burris HA Gordon MS Gerber DE Spigel DR Mendelson DS Schiller JH A phase I study of DNIB 0600A, an antibody-drug conjugate (ADC) targeting NaPi2b, in patients (pts) with non-small cell lung cancer (NSCLC) or platinum-resistant ovarian cancer (OC). J Clin Oncol 2014;32(Suppl; abstr 2504).

    Not in our library

  92. 92.

    Lin K Rubinfeld B Zhang C Firestein R Harstad E Roth L Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res 2015;21(22):5139–5150.

    Not in our library10.1158/1078-0432.ccr-14-3383

  93. 93.

    Gomez-Roca CA Boni V Moreno V Morris JC Delord JP Calvo E A phase I study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs)(NCT-01156870). J Clin Oncol 2016;34:2511.

    Not in our library

  94. 94.

    Ilovich O Natarajan A Hori S Sathirachinda A Kimura R Srinivasan A Development and validation of an immuno-PET tracer as a companion diagnostic agent for antibody-drug conjugate therapy to target the CA6 epitope. Radiology 2015;276(1):191–198.

    Not in our library10.1148/radiol.15140058

  95. 95.

    Kaufman JL Niesvizky R Stadtmauer EA Chanan-Khan A Siegel D Horne H Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma. Br J Haematol 2013; 163(4):478–486.

    Not in our library10.1111/bjh.12565

  96. 96.

    Kelly KR Chanan-Khan A Heffner LT Somlo G Siegel DS Zimmerman T Indatuximab ravtansine (BT062) in combination with lenalidomide and lowdose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in patients already exposed to lenalidomide and bortezomib. Blood 2014; 124(21):4736.

    Not in our library

  97. 97.

    Tai YT Mayes PA Acharya C Zhong MY Cea M Cagnetta A Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 2014;123(20): 3128–3138.

    Not in our library10.1182/blood-2013-10-535088

  98. 98.

    Khandelwal A Saber H Shapiro MA Zhao H Antibody-drug conjugate development. In: Phillips GL, editor. Antibody-drug conjugates and immunotoxins. New York: Human Press; 2013 p. 23–38.

    Not in our library

  99. 99.

    Xu S Internalization, trafficking, intracellular processing and actions of antibody-drug conjugates. Pharm Res 2015;32(11):3577–3583.

    Not in our library10.1007/s11095-015-1729-8

  100. 100.

    U.S. National Library of Medicine [Internet] Bethesda (MD): U.S. National Library of Medicine 2000 Feb -. A Study of DFRF4539A in Patients with Relapsed or Refractory Multiple Myeloma; 2016 11 02 [cited 2018 June 08]; [about 4 screens]. Available from: https://clinicaltrials.gov/ct2/show/NCT01432353.

    Not in our library

  101. 101.

    Gish K Kim H Power R Fox M Hickson J McGonigal T, editors. Preclinical evaluation of Abbv-838, a first-in-class anti-Cs1 antibody-drug conjugate for the treatment of multiple myeloma. Haematologica 2016; 101:253.

    Not in our library

  102. 102.

    Chanan-Khan A Wolf JL Garcia J Gharibo M Jagannath S Manfredi D Efficacy analysis from phase I study of lorvotuzumab mertansine (IMGN901), used as monotherapy, in patients with heavily pretreated CD56-positive multiple myeloma-a preliminary efficacy analysis. Blood 2010;116(21):1962.

    Not in our library

  103. 103.

    Doñate F Raitano A Morrison K An Z Capo L Aviña H AGS16F is a novel antibody drug conjugate directed against ENPP3 for the treatment of renal cell carcinoma. Clin Cancer Res 2016;22(8):1989–1999.

    Not in our library10.1158/1078-0432.ccr-15-1542

  104. 104.

    Thompson JA Motzer R Molina AM Choueiri TK Heath EI Kollmannsberger CK Phase I studies of anti-ENPP3 antibody drug conjugates (ADCs) in advanced refractory renal cell carcinomas (RRCC). J Clin Oncol 2015;33(Suppl 2503).

    Not in our library

  105. 105.

    Lassen U Hong D Diamantis N Subbiah V Kumar R Sorensen M A phase I, first-in-human study to evaluate the tolerability, pharmacokinetics and preliminary efficacy of HuMax-tissue factor-ADC (TFADC) in patients with solid tumors. J Clin Oncol 2015;33(Suppl; Abstr 2570).

    Not in our library

  106. 106.

    Thompson JA Motzer R Molina AM Choueiri TK Heath EI Kollmannsberger CK Phase I studies of anti-ENPP3 antibody drug conjugates (ADCs) in advanced refractory renal cell carcinomas (RRCC). J Clin Oncol 2015;33(Suppl 2503).

    Not in our library

  107. 107.

    Martin L Konner J Moore K Seward S Matulonis U Perez R Characterization of folate receptor alpha (FRα) expression in archival tumor and biopsy samples in a phase I study of mirvetuximab soravtansine, a FRα-targeting antibody-drug conjugate (ADC), in relapsed epithelial ovarian cancer patients. Gynecol Oncol 2017; 145:34.

    Not in our library10.1016/j.ygyno.2017.08.015

  108. 108.

    Moore KN Matulonis UA O'Malley DM Konner JA Martin LP Perez RP Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts. American Society of Clinical Oncology; 2017 J Clin Oncol 2017;35(no. 15):5547–5547.

    Not in our library10.1200/jco.2016.69.9538

  109. 109.

    Moore KN Ponte J LoRusso P Birrer MJ Bauer TM Borghaei H Relationship of pharmacokinetics (PK), toxicity, and initial evidence of clinical activity with IMGN853, a folate receptor alpha (FRa) targeting antibody drug conjugate in patients (Pts) with epithelial ovarian cancer (EOC) and other FRa-positive solid tumors. J Clin Oncol 2014;32(Suppl; Abstr 5571).

    Not in our library

  110. 110.

    O'Malley DM Moore KN Vergote I Martin LP Gilbert L Gonzalez Martin A Safety findings from FORWARD II: A Phase 1b study evaluating the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer. J Clin Oncol 2017;35:5553.

    Not in our library

  111. 111.

    Liu J Moore K Birrer M Berlin S Matulonis U Infante J Targeting MUC16 with the antibody-drug conjugate DMUC5754A in patients with platinum resistant ovarian cancer: A phase I study of safety and pharmacokinetics. AACR Annual Meeting; April 6–10; Washington, DC: 2013.

    Not in our library10.1093/annonc/mdw401

  112. 112.

    Goff LW Papadopoulos K Posey J Phan A Patnaik A Miller J A phase II study of IMGN242 (huC242-DM4) in patients with CanAg-positive gastric or gastroesophageal (GE) junction cancer. J Clin Oncol 2009;27(15S):e15625–e.

    Not in our library

  113. 113.

    Hong DS Garrido-Laguna I Krop IE Subbiah V Werner TL Cotter CM First-in-human dose escalation, safety, and PK study of a novel EFNA4-ADC in patients with advanced solid tumors. J Clin Oncol 2015; 33(15_suppl):2520.

    Not in our library

  114. 114.

    Annunziata CM Kohn EC LoRusso P Houston ND Coleman RL Buzoianu M Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors. Invest New Drugs 2013;31(1):77–84.

    Not in our library10.1007/s10637-012-9801-2

  115. 115.

    Jacobson O Niu G Kiesewetter DO Li Q Yang G Cook K PET-guided evaluation and optimization of internalized antibody-drug conjugates targeting erythropoietin producing hepatoma A2 receptor. J Nucl Med 2017;58(11):1838–1844.

    Not in our library10.2967/jnumed.117.192245

  116. 116.

    Challita-Eid PM Satpayev D Yang P An Z Morrison K Shostak Y Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76(10):3003–3013.

    Not in our library10.1158/0008-5472.can-15-1313

  117. 117.

    Rosenberg JE Heath EI Van Veldhuizen PJ Merchan JR Lang JM Ruether JD Anti-tumor activity, safety and pharmacokinetics (PK) of ASG-22CE (ASG-22ME; enfortumab vedotin) in a phase I dose escalation trial in patients (Pts) with metastatic urothelial cancer (mUC). J Clin Oncol 2016;34(15_suppl):4533–4533.

    Not in our library

  118. 118.

    Le PU Nabi IR Distinct caveolae-mediated endocytic pathways target the Golgi apparatus and the endoplasmic reticulum. J Cell Sc 2003;116(Pt 6):1059–1071.

    Not in our library10.1242/jcs.00327

  119. 119.

    Petrylak D Heath E Sonpavde G George S Morgans A Eigl B Interim analysis of a phase I dose escalation trial of the antibody drug conjugate (ADC) AGS15E (ASG-15ME) in patients (Pts) with metastatic urothelial cancer (mUC). Ann Oncol 2016;27(suppl 6): 780PD.

    Not in our library

  120. 120.

    Angevin E Strickler JH Weekes CD Phase I study of ABBV-399, a c-Met antibody-drug conjugate (ADC), as monotherapy and in combination with erlotinib in patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol 2017;35:2509.

    Not in our library

  121. 121.

    Doronina SO Toki BE Torgov MY Mendelsohn BA Cerveny CG Chace DF Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 2003;21(7):778–784.

    Not in our library10.1038/nbt832

  122. 122.

    Wang J Anderson MG Oleksijew A Vaidya KS Boghaert ER Tucker L ABBV-399, a c-Met antibody-drug conjugate that targets both MET-Amplified and c-Met-Overexpressing tumors, irrespective of MET pathway dependence. Clin Cancer Res 2017;23(4):992–1000.

    Not in our library10.1158/1078-0432.ccr-16-1568

  123. 123.

    Wang J Goetsch L Tucker L Zhang Q Gonzalez A Vaidya KS Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification. BMC Cancer 2016;16:105.

    Not in our library10.1186/s12885-016-2138-z

  124. 124.

    Sommer A Kopitz C Schatz CA Nising CF Mahlert C Lerchen HG Preclinical efficacy of the auristatin-based antibody-drug conjugate BAY 1187982 for the treatment of FGFR2-positive solid tumors. Cancer Res 2016;76(21):6331–6339.

    Not in our library10.1158/0008-5472.can-16-0180

  125. 125.

    Willuda J Linden L Lerchen H-G Kopitz C Stelte-Ludwig B Pena C Preclinical antitumor efficacy of BAY 1129980-a novel auristatin-based anti-C4. 4A (LYPD3) antibody-drug conjugate for the treatment of non-small cell lung cancer. Mol Cancer Ther 2017;16 (5):893–904.

    Not in our library10.1158/1535-7163.mct-16-0474

  126. 126.

    Menezes D Abrams TJ Karim C Tang Y Ying C Miller K Development and activity of a novel antibody-drug conjugate for the treatment of P-cadherin expressing cancers. Cancer Res 2015;75(15):1682.25769726

    Not in our library

  127. 127.

    Shapiro GI Vaishampayan UN LoRusso P Barton J Hua S Reich SD First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors. Invest New Drugs 2017;35(3):315–323.

    Not in our library10.1007/s10637-016-0419-7

  128. 128.

    Danila DC Fleisher M Carrasquillo JA Gilbert H Morris MJ Bellomo LP STEAP1 as a predictive biomarker for antibody-drug conjugate (ADC) activity in metastatic castration resistant prostate cancer (m-CRPC). J Clin Oncol 2014;32(Suppl; Abstr 5024).

    Not in our library

  129. 129.

    Danila DC Scher HI Szafer-Glusman E Herkal A Suttmann R Fleisher M Predictive biomarkers of tumor sensitivity to STEAP1 antibody-drug conjugate (ADC) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). AACR 106th Annual Meeting 2015; April 18–22, 2015; Philadelphia, PA.

    Not in our library

  130. 130.

    Danila DC Szmulewitz RZ Baron AD Higano CS Scher HI Morris MJ A phase I study of DSTP-3086S, an antibody-drug conjugate (ADC) targeting STEAP-1, in patients (pts) with metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 2014; 32(Suppl; abstr 5024).

    Not in our library

  131. 131.

    Williams SP Ogasawara A Tinianow JN Flores JE Kan D Lau J ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. Oncotarget 2016;7(18):25103–25112.

    Not in our library10.18632/oncotarget.8390

  132. 132.

    Damelin M Bankovich A Bernstein J Lucas J Chen L Williams S A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci Transl Med 2017;9(372). pii: eaag2611.

    Not in our library10.1126/scitranslmed.aag2611

  133. 133.

    Sachdev J Maitland M Sharma M Moreno V Boni V Kummar S A phase 1 study of PF-06647020, an antibody-drug conjugate (ADC) targeting protein tyrosine kinase 7 (PTK7), in patients with advanced solid tumors including platinum resistant ovarian cancer (OVCA). Ann Oncol 2016;27(suppl 6):LBA35.

    Not in our library

  134. 134.

    Damelin M Bankovich A Park A Aguilar J Anderson W Santaguida M Anti-EFNA4 calicheamicin conjugates effectively target triple-negative breast and ovarian tumor-initiating cells to result in sustained tumor regressions. Clin Cancer Res 2015;21(18):4165–4173.

    Not in our library10.1158/1078-0432.ccr-15-0695

  135. 135.

    Sussman D Smith LM Anderson ME Duniho S Hunter JH Kostner H SGN–LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther 2014;13 (12):2991–3000.

    Not in our library10.1158/1535-7163.mct-13-0896

  136. 136.

    Alley SC Zhang X Okeley NM Anderson M Law CL Senter PD The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther 2009;330(3):932–938.

    Not in our library10.1124/jpet.109.155549

  137. 137.

    Deckert J Park PU Chicklas S Yi Y Li M Lai KC A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of Bcell malignancies. Blood 2013;122(20):3500–3510.

    Not in our library10.1182/blood-2013-05-505685

  138. 138.

    English DP Bellone S Schwab CL Bortolomai I Bonazzoli E Cocco E T-DM1, a novel antibody-drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo. Cancer Med 2014;3(5):1256–1265.

    Not in our library10.1002/cam4.274

  139. 139.

    Boswell CA Mundo EE Firestein R Zhang C Mao W Gill H An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2. Br J Pharmacol 2013;168 (2):445–457.

    Not in our library10.1111/j.1476-5381.2012.02138.x

  140. 140.

    The ASCO Post [Internet] Huntington: HSP News Service, L.L.C., Phase I Trial of New Antibody-Drug Conjugate Shows Promise Against All Forms of Melanoma; 2014 8 04 [cited 2018 June 08]; [about 2 screens]. Available from: http://www.ascopost.com/News/15102.

    Not in our library

  141. 141.

    Bendell J Moore K Qin A Johnson D Schindler J Papadopoulos K 472 A phase I study of IMGN-388, an antibody drug conjugate targeting av integrin, in patients with solid tumors. Eur J Cancer Suppl 2010;8 (7):152.

    Not in our library

  142. 142.

    Kelly RK Olson DL Sun Y Wen D Wortham KA Antognetti G An antibody-cytotoxic conjugate, BIIB015, is a new targeted therapy for Cripto positive tumours. Eur J Cancer 2011;47(11):1736–1746.

    Not in our library10.1016/j.ejca.2011.02.023

  143. 143.

    Coveler AL Von Hoff DD Ko AH Whiting NC Zhao B Wolpin BM A phase I study of ASG-5ME, a novel antibody-drug conjugate, in pancreatic ductal adenocarcinoma. J Clin Oncol 2013;31(Suppl 4; abstr 176).

    Not in our library

  144. 144.

    Modi S Eder JP Lorusso P Weekes C Chandarlapaty S Tolaney SM A phase I study evaluating DLYE-5953A, an antibody-drug conjugate targeting the tumor-associated antigen lymphocyte antigen 6 complex locus E (Ly6E), in patients (Pts) with solid tumors. Ann Oncol 2016;27(suppl_6):3570.

    Not in our library

  145. 145.

    Lassen UN Ramalingam SS Lopez JS Harvey RD Ameratunga M de Hoon J GCT1021–01, a firstin-human, open-label, dose-escalation trial with expansion cohorts to evaluate safety of Axl-specific antibody-drug conjugate (HuMax-Axl-ADC) in patients with solid tumors (NCT02988817). J Clin Oncol 2017;35:TPS2605.

    Not in our library

  146. 146.

    Canzonieri V Gattei V Spina M Polizzi-Anselmo A Attanasio N Kaplan A CD205, a target antigen for a novel antibody drug conjugate (ADC): Evaluation of antigen expression on non-Hodgkin lymphoma (NHL). J Clin Oncol 2017;35(15_suppl): published online before print.

    Not in our library

  147. 147.

    Horwitz SM Fanale MA Spira AI Havenith K He S Feingold JM Interim data from the first clinical study of ADCT-301, a novel pyrrplomenzodiaza-pine-based antibody drug conjugate, in relapsed/refractory hodgkin/non-hodgkin lymphoma. Hematol Oncol 2017; 35(S2):270–271.

    Not in our library

  148. 148.

    Baudat Y Cameron B Dabdoubi T Lefebvre AM Merino-Trigo A Thomas C, editors. Characterization of a novel maytansinoid-antibody-drug conjugate targeting LAMP1 expressed at the surface of tumor cells. 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16–20; New Orleans, LA Philadelphia: American Association for Cancer Research; 2016.

    Not in our library

  149. 149.

    Petrul HM Schatz CA Kopitz CC Adnane L McCabe TJ Trail P Therapeutic mechanism and efficacy of the antibody-drug conjugate BAY 79–4620 targeting human carbonic anhydrase 9. Mol Cancer Ther 2012;11 (2):340–349.

    Not in our library10.1158/1535-7163.mct-11-0523

  150. 150.

    Herbst R Wang Y Gallagher S Mittereder N Kuta E Damschroder M B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther 2010;335(1):213–222.

    Not in our library10.1124/jpet.110.168062

  151. 151.

    Cardarelli PM Rao-Naik C Chen S Huang H Pham A Moldovan-Loomis M-C A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies. Cancer Immunol Immunother 2010;59(2):257–265.

    Not in our library10.1007/s00262-009-0746-z

  152. 152.

    Horton HM Bernett MJ Pong E Peipp M Karki S Chu SY Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res 2008;68(19): 8049–8057.

    Not in our library10.1158/0008-5472.can-08-2268

  153. 153.

    Awan FT Lapalombella R Trotta R Butchar JP Yu B Benson DM CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain–engineered monoclonal antibody. Blood 2010;115(6):1204–1213.

    Not in our library10.1182/blood-2009-06-229039

  154. 154.

    Reichert JM Bispecific antibodies and ADCs: once and future kings? MAbs 2011;3(4):329–330.

    Not in our library10.4161/mabs.3.4.16589

  155. 155.

    Golay J D’Amico A Borleri G Bonzi M Valgardsdottir R Alzani R A novel method using blinatumomab for efficient, clinical-grade expansion of polyclonal T cells for adoptive immunotherapy. J Immunol 2014; 193(9):4739–4747.

    Not in our library10.4049/jimmunol.1401550

  156. 156.

    Ng G Spreter T Davies R Wickman G ZW38, a novel azymetric bispecific CD19-directed CD3 T cell engager antibody drug conjugate with controlled T cell activation and improved B cell cytotoxicity. Blood 2016;128 (22):1841.

    Not in our library

  157. 157.

    Sellmann C Doerner A Knuehl C Rasche N Sood V Krah S Balancing selectivity and efficacy of bispecific epidermal growth factor receptor (EGFR)× c-MET antibodies and antibody-drug conjugates. J Biol Chem 2016;291(48):25106–25119.

    Not in our library10.1074/jbc.m116.753491

  158. 158.

    Sierra JR Tsao MS c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol 2011;3(1 suppl):S21–S35.

    Not in our library10.1177/1758834011422557

  159. 159.

    Andreev J Thambi N Bay AEP Delfino F Martin J Kelly MP Bispecific antibodies and antibody-drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol Cancer Ther 2017;16(4):681–693.

    Not in our library10.1158/1535-7163.mct-16-0658

  160. 160.

    Azvolinsky A Conjugating antibodies to cytotoxic agents: getting the best of both worlds? J Natl Cancer Inst 2013;105(23):1765–1766.

    Not in our library10.1093/jnci/djt354

  161. 161.

    Chari RJ Goldmacher VS Lambert JM Blattler WA, inventors; Google Patents, assignee. Cytotoxic agents comprising maytansinoids and their therapeutic use. United States patent US 5,416,064 A. 1995 5 16.

    Not in our library

  162. 162.

    Sullivan R Paré GC Frederiksen LJ Semenza GL Graham CH Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther 2008;7(7):1961–1973.

    Not in our library10.1158/1535-7163.mct-08-0198

  163. 163.

    Widdison WC Chari RVJ Factors involved in the design of cytotoxic payloads for antibody-drug conjugates. In: Phillips G, editor. Antibody-Drug Conjugates and Immunotoxins. New York: Human Press; 2013 p. 93–115.

    Not in our library

  164. 164.

    Vankemmelbeke M Durrant L Third-generation antibody drug conjugates for cancer therapy--a balancing act. Ther Deliv 2016;7(3):141–144.

    Not in our library10.4155/tde-2016-0002

  165. 165.

    Govindan SV Goldenberg DM Designing immunoconjugates for cancer therapy. Expert Opin Biol Ther 2012;12(7):873–890.

    Not in our library10.1517/14712598.2012.685153

  166. 166.

    Maurya DK Ayuzawa R Doi C Troyer D Tamura M Topoisomerase I inhibitor SN-38 effectively attenuates growth of human non-small cell lung cancer cell lines invitro and in vivo. J Environ Pathol Toxicol Oncol 2011;30(1):1–10.

    Not in our library10.1615/jenvironpatholtoxicoloncol.v30.i1.10

  167. 167.

    Cardillo TM Govindan SV Sharkey RM Trisal P Arrojo R Chang CH Sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate: Characterization and efficacy in pancreatic, gastric, and other cancers. Bioconjug Chem 2015;26(5): 919–931.

    Not in our library10.1021/acs.bioconjchem.5b00223

  168. 168.

    Cardillo TM Govindan SV Sharkey RM Trisal P Goldenberg DM Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res 2011;17(10): 3157–3169.

    Not in our library10.1158/1078-0432.ccr-10-2939

  169. 169.

    Sharkey RM Govindan SV Cardillo TM Goldenberg DM Epratuzumab-SN-38: a new antibody-drug conjugate for the therapy of hematologic malignancies. Mol Cancer Ther 2012;11(1):224–234.

    Not in our library10.1158/1535-7163.mct-11-0632

  170. 170.

    Acchione M Kwon H Jochheim CM Atkins WM Impact of linker and conjugation chemistry on antigen binding, Fc receptor binding and thermal stability of model antibody-drug conjugates. MAbs 2012;4(3):362–372.

    Not in our library10.4161/mabs.19449

  171. 171.

    Sochaj AM Świderska KW Otlewski J Current methods for the synthesis of homogeneous antibody-drug conjugates. Biotechnol Adv 2015;33(6 Pt 1):775–784.

    Not in our library10.1016/j.biotechadv.2015.05.001

  172. 172.

    Wang L Amphlett G Blättler WA Lambert JM Zhang W Structural characterization of the maytansinoid monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. Protein Sci 2005;14(9):2436–2446.

    Not in our library10.1110/ps.051478705

  173. 173.

    Junutula JR Raab H Clark S Bhakta S Leipold DD Weir S Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 2008b;26(8):925–932.

    Not in our library10.1038/nbt.1480

  174. 174.

    Schroeder DD Tankersky DL Lundblad JL A new preparation of modified immune serum globulin (human) suitable for intravenous administration. Vox Sang 1981;40(6):373–382.

    Not in our library10.1111/j.1423-0410.1981.tb00725.x

  175. 175.

    Willner D Trail PA Hofstead SJ King HD Lasch SJ Braslawsky GR (6-Maleimidocaproyl)hydrazone of doxorubicin--a new derivative for the preparation of immunoconjugates of doxorubicin. Bioconjug Chem 1993;4(6):521–527.

    Not in our library10.1021/bc00024a015

  176. 176.

    Junutula JR Bhakta S Raab H Ervin KE Eigenbrot C Vandlen R Rapid identification of reactive cysteine residues for site-specific labeling of antibody-Fabs. J Immunol Methods 2008;332(1–2):41–52.

    Not in our library10.1016/j.jim.2007.12.011

  177. 177.

    Hofer T Skeffington LR Chapman CM Rader C Molecularly defined antibody conjugation through a selenocysteine interface. Biochemistry 2009;48(50):12047–12057.

    Not in our library10.1021/bi901744t

  178. 178.

    Axup JY Bajjuri KM Ritland M Hutchins BM Kim CH Kazane SA Synthesis of site-specific antibody-drug conjugates using unnatural amino acids. Proc Natl Acad Sci USA 2012;109(40):16101–16106.

    Not in our library10.1073/pnas.1211023109

  179. 179.

    Okeley NM Toki BE Zhang X Jeffrey SC Burke PJ Alley SC Metabolic engineering of monoclonal antibody carbohydrates for antibody-drug conjugation. Bioconjug Chem 2013;24(10):1650–1655.

    Not in our library10.1021/bc4002695

  180. 180.

    Zhu Z Ramakrishnan B Li J Wang Y Feng Y Prabakaran P Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar. MAbs 2014;6(5):1190–200.

    Not in our library10.4161/mabs.29889

  181. 181.

    Zhou Q Stefano JE Manning C Kyazike J Chen B Gianolio DA Site-specific antibody-drug conjugation through glycoengineering. Bioconjug Chem 2014; 25(3):510–520.

    Not in our library10.1021/bc400505q

  182. 182.

    Drake PM Albers AE Baker J Banas S Barfield RM Bhat AS Aldehyde tag coupled with HIPS chemistry enables the production of ADCs conjugated site-specifically to different antibody regions with distinct in vivo efficacy and PK outcomes. Bioconjug Chem 2014; 25(7):1331–1341.

    Not in our library10.1021/bc500189z

  183. 183.

    Dennler P Chiotellis A Fischer E Brégeon D Belmant C Gauthier L Transglutaminase-based chemoenzymatic conjugation approach yields homogeneous antibody-drug conjugates. Bioconjug Chem 2014;25(3): 569–578.

    Not in our library10.1021/bc400574z

  184. 184.

    Spidel J Vaessen B Albone E Cheng X Verdi A Kline JB Site-Specific conjugation to native and engineered lysines in human immunoglobulins by microbial transglutaminase. Bioconjug Chem 2017;28(9):2471–2484.

    Not in our library10.1021/acs.bioconjchem.7b00439

  185. 185.

    Strop P Liu SH Dorywalska M Delaria K Dushin RG Tran TT Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol 2013;20(2):161–167.

    Not in our library10.1016/j.chembiol.2013.01.010

  186. 186.
    Sortase Enzyme-Mediated Generation of Site-Specifically Conjugated Antibody Drug Conjugates with High In Vitro and In Vivo Potency · 2015
    No notice
  187. 187.

    Grünewald J Klock HE Cellitti SE Bursulaya B McMullan D Jones DH Efficient preparation of site-specific antibody-drug conjugates using phosphopantetheinyl transferases. Bioconjug Chem 2015;26(12): 2554–2562.

    Not in our library10.1021/acs.bioconjchem.5b00558

  188. 188.

    Tang F Wang LX Huang W Chemoenzymatic synthesis of glycoengineered IgG antibodies and glycosite-specific antibody-drug conjugates. Nat Protoc 2017;12 (8):1702–1721.

    Not in our library10.1038/nprot.2017.058

  189. 189.

    McCombs JR Owen SC Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J 2015;17(2):339–351.

    Not in our library10.1208/s12248-014-9710-8

  190. 190.

    Ritter A Antibody-drug conjugates: looking ahead to an emerging class of biotherapeutic. Pharm Technol 2012; 36(1):42–47.

    Not in our library

  191. 191.

    Dyba M Tarasova NI Michejda CJ Small molecule toxins targeting tumor receptors. Curr Pharm Des 2004; 10(19):2311–2334.

    Not in our library10.2174/1381612043384024

  192. 192.

    Goldmacher VS Singh R Chittenden T Kovtun Y Linker technology and impact of linker design on ADC properties. In: Phillips GL, editor. Antibody-drug conjugates and immunotoxins. New York: Human Press; 2013 p. 117–135.

    Not in our library

  193. 193.

    Erickson HK Lambert JM ADME of antibody-maytansinoid conjugates. AAPS J 2012;14(4):799–805.

    Not in our library10.1208/s12248-012-9386-x

  194. 194.

    Kovtun YV Audette CA Mayo MF Jones GE Doherty H Maloney EK Antibody-maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res 2010;70(6):2528–2537.

    Not in our library10.1158/0008-5472.can-09-3546

  195. 195.

    Sun X Ponte JF Yoder NC Laleau R Coccia J Lanieri L Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibodymaytansinoid conjugates. Bioconjug Chem 2017; 28(5):1371–1381.

    Not in our library10.1021/acs.bioconjchem.7b00062

  196. 196.

    van Geel R Wijdeven MA Heesbeen R Verkade JM Wasiel AA van Berkel SS Chemoenzymatic conjugation of toxic payloads to the globally conserved nglycan of native mAbs provides homogeneous and highly efficacious antibody-drug conjugates. Bioconjug Chem 2015;26(11):2233–2242.

    Not in our library10.1021/acs.bioconjchem.5b00224

  197. 197.

    Zimmerman ES Heibeck TH Gill A Li X Murray CJ Madlansacay MR Production of site-specific antibody-drug conjugates using optimized non-natural amino acids in a cell-free expression system. Bioconjug Chem 2014;25(2):351–361.

    Not in our library10.1021/bc400490z

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