What are Antibody-drug Conjugates? | ADC Review (2023)

What are Antibody-drug Conjugates? | ADC Review (1)

Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.

With12 approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.


Antibody-drug Conjugates (ADC) 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 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 specific cancer cell to 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

Mechanistically, antibody-drug conjugates exert their activity by (1) selective binding of the antibody to tumor, (2) internalization and (3) lysosomal degradation, and release of the cytotoxic payload, leading to cytotoxic cell death.

01: An Innovative Therapeutic Application

Antibody-drug conjugates or ADCs are a new class of highly potent biopharmaceutical drug composed of an antibody linked, via a chemical linker, to a biologically active drug or cytotoxic compound. Thes targeted agents combine the unique and very sensitive targeting capabilities of antibodies allowing sensitive discrimination between healthy and cancer tissues with the cell-killing ability of cytotoxic drugs.

To date, ten antibody-drug conjugates have received market approval and nearly 100 investigational ADCs are currently in pre-clinical and clinical trials.

(Video) What are Antibody-drug Conjugates (ADCs)?

Antibody-drug conjugates represent an innovative therapeutic application that combines the unique, high specificity, properties, and anti-tumor activity of monoclonal antibodies (mAbs) that are tumor-specific but not sufficiently cytotoxic, with the potent cell-killing activity of highly cytotoxic small molecule drugs that are unsuitable for systemic administration alone.

Because these agents are capable of delivering highly cytotoxic payloads directly to tumor cells they can be used to achieve high lethality toward the targeted cancer cells while leaving healthy cells unharmed.

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 disulfideornon-cleavable thioetherlinker 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.

Figure 1.1: Biotechnology + Chemistry = Antibody-Drug Conjugates. Image Courtesy: Lonza. Adapted from Rohrer T. [5]

02: The Make-up of an ADC

Monoclonalantibodies 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 aspecialized and technically challengingtype 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-calledarmed antibodiesselectively dispatch highly potent cytotoxic anticancer chemotherapies directly to cancer cells while, at the same time, leaving healthy tissue unaffected. [1,2]

03: Availability

With the approvals of gemtuzumab Ozogamicin (Mylotarg®; Wyeth Pharmaceuticals, a subsidiary of Pfizer), brentuximab vedotin(Adcetris®; Seattle Genetics/Millennium Pharmaceuticals),ado-trastuzumab emtansine(Kadcyla®; Genentech/Roche),inotuzumab ozogamicin (Besponsa®; Wyeth Pharmaceuticals, a subsidiary of Pfizer), Enfortumab vedotin (Padcev™; Astellas Pharma / Seattle Genetics), Fam-trastuzumab deruxtecan-nxki (Enhertu®; Daiichi Sankyo and AstraZeneca), Polatuzumab vedotin-piiq (Polivy™; Genentech/Roche), sacituzumab govitecan (sacituzumab govitecan-hziy; Trodelvy™; Immunomedics)and more than 80 ADCs in current clinical trial pipelines, ADCs are a new drug class. Owing to improved technology and appropriate targeting, the clinical application of ADCs is accelerating rapidly.[3]

(Video) A View On Antibody-Drug Conjugates

Conventional chemotherapy is designed to eliminate fast-growing tumor cells. It can, however, also harm healthy proliferating cells, which causes undesirable side effects. [4] In contrast, ADCs are designed to increase the efficacy of therapy and reduce systemic toxicity, often seen with small molecule drugs.

04: Linker technology

Antibody-Drug Conjugatesdeliverhighly potent cytotoxic anticancer agentsto cancer cells by joining them to monoclonal antibodies by biodegradable,stable linkersand 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.

05: How they work

The antibody-drug conjugate is a three-component system including apotent 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. [1]

Themechanism of action (MOA) of antibody-drug conjugatesis rather simple. When some portion of the antibody-drug conjugate isadministered 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 theendosome-lysosome pathway. In the lysosome, proteases in a 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. [4]

06: 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.

(Video) How Does It Work? | Antibody Drug Conjugates

07: 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. [5] 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.

08: 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 generallyless cytotoxic for the targeted tumor cells than the corresponding unconjugated agents.

To solve this problem, scientists started to look atcompounds 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 arehighly potent, biologically active anti-microtubule agents, alkylating agents, and DNA minor groove binding agents are being used in combination with 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 theinhibitors of tubulin polymerization such as the maytansinoids(maytansine;DMs),dolastatins,auristatindrug analogs, and cryptophycin are related to their ability to inhibit cell division by binding tubulin, which arrests the target cell in the G2/M stage of the cell cycle resulting in apoptosis. These agents include the duocarmycin derivatives such asCC-1065 analogsandduocarmycinare DNA alkylating agents, the enediyne antibioticsincluding esperamicinandcalicheamicinwhich catalyze DNA double-strand breaks and pyrrolobenzodiazepine (PBD), a DNA minor groove binding agent. Pyrolobenodiazepine (PBD) has shownin vitro cytotoxic potency against human tumor cell lines at 20pmol/L in the cell culture medium. [6]

What are Antibody-drug Conjugates? | ADC Review (8)

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(Video) Antibody Drug Conjugates: The end of chemotherapy | 2023 West Oncology Conference


What are Antibody-drug Conjugates? | ADC Review? ›

Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.

What are drug antibody conjugates? ›

A substance made up of a monoclonal antibody chemically linked to a drug. The monoclonal antibody binds to specific proteins or receptors found on certain types of cells, including cancer cells. The linked drug enters these cells and kills them without harming other cells.

What are ADCs and how they are produced? ›

An antibody-drug conjugate (ADC) is formed by covalent biochemical conjugation of a monoclonal antibody with highly toxic payload drugs via a small molecular linker.

What are antibody drug conjugate challenges? ›

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.

Why are antibody-drug conjugates important? ›

ADCs synergistically play the “specific” targeting role and the “efficient” killing effect on cancer cells. Such drugs are like a precision guided “biological missile” with the ability to destroy cancer cells accurately, improving the therapeutic window and reducing the off-targeted side effects.

What are the three main components of an antibody drug conjugate? ›

The key components of antibody-drug conjugates include a monoclonal antibody, a stable linker, and a cytotoxic agent to target a variety of cancers.

How do antibody conjugates work? ›

Antibody–drug conjugates (ADCs) are complex targeted agents composed by a cytotoxic drug hanging on an antibody scaffold. Upon binding with the cell surface antigen targeted by the specific antibody, the ADC is internalized by the tumor cell and processed by the endo-lysosomal system.

How are antibody drug conjugates made? ›

Antibody drug conjugates (ADCs) are synthesized by conjugating a cytotoxic drug or “payload” to a monoclonal antibody. The payloads are conjugated using amino or sulfhydryl specific linkers that react with lysines or cysteines on the antibody surface.

What is antibody drug example? ›

For example, trastuzumab (Herceptin) and rituximab (Mabthera). Some MABS help the immune system to attack and kill cancer cells.

What are ADCs explained? ›

In electronics, an analog-to-digital converter (ADC, A/D, or A-to-D) is a system that converts an analog signal, such as a sound picked up by a microphone or light entering a digital camera, into a digital signal.

What are the roles of ADCs? ›

An ADC essentially functions as a load balancer, optimizing end-user performance, reliability, data center resource use and security for enterprise applications.

What are the benefits of ADCs? ›

What are the advantages of ADCs?
  • Increased tumor specificity and selectivity, resulting in increased drug tolerability and limited systemic exposure.
  • Increased cytotoxic potency, due to the specificity of antibodies, ADCs can carry payloads that are too toxic for systemic administration.
Jan 10, 2022

What effect does conjugation have on a drug? ›

Conjugation. Glucuronidation, the most common phase II reaction, is the only one that occurs in the liver microsomal enzyme system. Glucuronides are secreted in bile and eliminated in urine. Thus, conjugation makes most drugs more soluble and easily excreted by the kidneys.

Why are drugs conjugated? ›

Abstract. Conjugation is an important mechanism for the rapid inactivation and extensive removal of drugs and poisons from the body, and as such it is of major significance in clinical toxicology.

How many antibody drug conjugates are approved? ›

As of May 2021, the U.S. Food and Drug Administration (FDA) has approved ten ADCs, namely Adcetris®, Kadcyla®, Besponsa®, Mylotarg®, Polivy®, Padcev®, Enhertu®, Trodelvy®, Blenrep®, and Zynlonta™ as monotherapy or combinational therapy for breast cancer, urothelial cancer, myeloma, acute leukemia, and lymphoma.

What is the difference between chemotherapy and ADC? ›

Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells.


1. Antibody Drug Conjugates
2. Are You Prepared for the New Wave of ADCs in NSCLC? Targeting HER2, HER3, TROP2, and Others
(PeerView Oncology)
3. Antibody-drug conjugates (ADCs) in NSCLC
4. Antibody-drug Conjugate-Precision Targeted Therapy - Creative Biolabs
(Creative Biolabs)
5. Antibody Drug Conjugates: Science and Imagination Linked by Purpose
6. ADC Review / Journal of Antibody-drug Conjugates
(ADC Review / Journal of Antibody-drug Conjugates)
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