Antibody Drug Conjugates

• Introduction

Antibody-drug Conjugates or ADCs are empowered antibodies (mAbs) designed to harness the targeting ability of monoclonal antibodies by linking them to cell-killing agents. An ideal ADC has:

  • A highly selective monoclonal antibody (mAb) for a tumor-associated antigen that has restricted or no expression on normal (healthy) cells;
  • A potent cytotoxic agent (generally a small molecule drug with a high systemic toxicity) designed to induce target cell death after being internalized in the tumor cell and released;
  • A linker that is stable in circulation, but releases the cytotoxic agent in target cells.
  • Antibody-drug Conjugates
  • Covalently linked monoclonal antibodies to small molecule drugs that target the a specific cancer cell reduce systemic toxicity
  • Increase the cell-killing potential of monoclonal antibodies (mAbs), and
  • Confer higher tumor selectivity. As a result, the tolerability of the drug increases.
  • Compared to standard chemotherapeutic drugs or biologics, there is limited systemic exposure

• Innovative Therapeutic Application

Antibody-drug conjugates or ADCs represent an innovative therapeutic application that combines the unique, high specificity, properties and antitumor activity of monoclonal antibodies (mAbs) that are tumor-specific but not sufficiently cytotoxic, with the potent cell killing activity of cytotoxic small molecule drugs that are too toxic to be used on their own. In linking monoclonal antibodies with cytotoxic agents, scientists have been able to optimize the features of both components.

The key components of antibody-drug conjugates include a monoclonal antibody, a stable linker and a cytotoxic agent to target a variety of cancers. The cytotoxic (anticancer) drug is chemically linked (conjugated using disulfide or non-cleavable thioether linker chemistry) to a monoclonal antibody that recognizes a specific tumor-associated antigen, making the drug combination very specific. In simple terms, antibody-drug conjugates deliver “deactivated” cytotoxins to specific cancer cells. Once in the tumor cell – internalization – the cytotoxin is released after which it regains its full – cancer killing – cytotoxic activity. In turn, this leads to rapid cell death.

While the concept of antibody-drug conjugates is relatively easy to understand and relatively straightforward, the design and synthesis of a fully functional and effective antibody-drug conjugate is remarkably challenging, often requiring specialized development teams.

• The Make-up of an ADC

Monoclonal antibodies are attached to biologically active drugs by chemical linkers with labile bonds.  By combining the unique targeting of mAbs with the cancer-killing ability of cytotoxic drugs, antibody-drug conjugates allow sensitive discrimination between healthy and diseased tissue.  Antibody-drug conjugates are part of a specialized and technically challenging type of therapy combining innovations from biotechnology and chemistry to form a new class of highly potent biopharmaceutical drugs.

The unique property of antibody-drug conjugates is that these so-called armed antibodies selectively dispatch highly potent cytotoxic anticancer chemotherapies directly to cancer cells while, at the same time, leaving healthy tissue unaffected.

• Availability

With the approvals of Brentuximab vedotin (Adcetris®; Seattle Genetics/Millennium Pharmaceuticals) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) and more than 50 ADCs in clinical trial pipelines, ADCs are a new drug class. Owing to improved technology and appropriate targeting, the clinical application of ADCs is accelerating rapidly.

Conventional chemotherapy is designed to eliminate fast -growing tumor cells. It can however, also harm healthy proliferating cells, which causes undesirable side effects. In contrast, ADCs are designed to increase the efficacy of therapy and reduce systemic toxicity, often seen with small molecule drugs.

 àLinker technology

Antibody-Drug Conjugates deliver highly potent cytotoxic anticancer agentss to cancer cells by joining them to monoclonal antibodies by biodegradable, stable linkers and discriminate between cancer and normal tissue. These linkers are either cleavable or non-cleavable.

Advances in linker technology needed to attach monoclonal antibodies to cytotoxic anticancer agents to allow control over drug pharmacokinetics and significantly improve delivery of a cytotoxic agent to cancer cells.

• Mechanism of Action

The antibody-drug conjugate is a three-component system including a potent cytotoxic anticancer agent linked via a biodegradable linker to an antibody. The antibody binds to specific markers (antigens or receptors) at the surface of the cancer cell. The whole antibody-drug conjugate is then internalized within the cancer cell, where the linker is degraded and the active drug released.

The focused delivery of the cytotoxic agent to the tumor cell is designed to maximize the anti-tumor effect of ADCs, while minimizing its normal tissue exposure, potentially leading to an improved therapeutic index.

The mechanism of action (MOA) of antibody-drug conjugates is rather simple. When some portion of the antibody-drug conjugate is administered intravenously localizes to a tumor and binds to a target antigen on the cell-surface of the tumor cell, the complex will be internalized into the cell. Following internalization, the internalized vesicles fuse with other vesicles and enter the endosome-lysosome pathway. In the lysosome, proteases in mild acidic environment digest the monoclonal antibody to release free payloads, which then cross the lysosome membrane to enter the cytoplasm and/or the nucleus where they bind to the target molecule which, in turn, leads to cell death.  

• Specificity and efficacy

The efficacy of antibody-targeted chemotherapy greatly depends on the specific binding of the targeting antibody-drug conjugate to the specific tumor antigen and on the internalization of the antigen-antibody complex to ensure focused delivery of the conjugated cytotoxic agent inside tumor cells.

The focused delivery of the cytotoxic agent to tumor cells maximizes the antitumor effect. It also minimizes normal tissue exposure that results in an improved therapeutic index and less damage to the surrounding, healthy tissue.

• Antibody affinity

The monoclonal antibody affinity, the strength with which an antibody binds to an epitope (antigenic determinant), to the selected antigen is an important factor in ADCs. So-called high-affinity antibodies may have a greater uptake, increasing the therapeutic advantage. However, while the uptake by the ‘outer layer’ of antigen-positive cells may be higher, the penetration and distribution throughout a ‘bulky tumors’ may be reduced.

• Cytotoxic drugs

There are thousands of cellular toxins from either natural sources or chemical synthesis, but only a very few are suitable as components for use in an Antibody-drug Conjugate (ADCs).  In the development of early ADCs, researchers used clinically approved chemotherapeutic drugs. One reason is that these agents  were readily available and their toxicological properties were well known.

However, these early ADCs were only moderately potent and generally less cytotoxic for the targeted tumor cells than the corresponding unconjugated agents.

To solve this problem, scientists started to look at compounds found to be too toxic when tested as a stand-alone chemotherapeutic agent. But the number of these high potent toxins, generally 100 to 1,000 times more toxic than traditional anticancer agents, and are stable, is quite limited.

Among these are highly potent, biologically active anti-microtubule agents, alkylating agents and DNA minor groove binding agents are being used in combination to humanized mAb targeting agents. These drugs are biologically active at the ng/Kg level placing them in the most potent class of advanced cancer drugs.


The cytotoxicity of the inhibitors of tubulin polymerization such as the maytansinoids (maytansine; DMs), dolastatinsauristatin drug analogues and cryptophycinn are related to their ability to inhibit cell division by binding tubulin, which arrest the target cell in the G2/M stage of the cell cycle resulting in apoptosis. The agents include the duocarmycin deriatives such as CC-1065 analogs and duocarmycin are DNA alkylating agents, the enediyne antibiotics including esperamicin and calicheamicin which catalyze DNA double-strand breaks and pyrolobenodiazepine (PBD), a DNA minor groove binding agent. Pyrolobenodiazepine (PBD) has shown in vitro cytotoxic potency against human tumor cell lines at 20pmol/L in cell culture medium.

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