Research and development of antibody-drug conjugates (ADCs) are a hotbed of activity and investment in cancer treatments. As a mechanism for delivering anti-cancer agents directly to cells containing a specified target antigen, ADCs represent a long-sought therapeutic approach in oncology. 

 

The road to approvals

 

A review article in Nature Reviews Clinical Oncology traces the history of these products and presents the current state of knowledge about ADCs as a treatment class.

Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021 Jun;18(6):327-344.

 

It wasn’t until the FDA approved the CD33-targeted agent gemtuzumab ozogamicin for relapsed/refractory (R/R) acute myeloid leukemia in 2000 that ADCs became a clinical reality. This specific ADC, however, was voluntarily withdrawn from the market in 2010 due to concerns that adverse events outweighed efficacy. 

In 2011, the CD30-targeted ADC brentuximab vedotin was greenlighted by the FDA for the treatment of R/R classical Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. Shortly thereafter, the HER2-targeted ADC ado-trastuzumab emtansine (T-DM1) was approved for the treatment of trastuzumab-resistant metastatic breast cancer. In the ensuing years, several ADCs have been approved.

 

Defining ADCs

 

Antibody-drug conjugates (ADCs) consist of a small-molecule drug (ie, the payload) conjugated to an antibody fragment (ie, antibody) by a chemical linker. As explained in a draft guidance by the FDA, the antibody is engineered against a specific antigen target that exists on the cell surface; this antigen, specific to the disease state being treated, is thus a tumor-specific antigen.

Clinical Pharmacology Considerations for Antibody-Drug Conjugates. Draft Guidance for Industry. FDA. February 2022.

 

Typically, the antibody binds to the target antigen, and the ADC is introduced into the cancer cell via endocytosis. The payload is then released when it is exposed to the low pH of the lysosome or by breakdown of the antibody/linker via lysosomal enzymes. 

 

Four examples of ADCs

 

Polatuzumab vedotin (Polivy)

This ADC selectively binds to CD79b after endocytosis and proteolytic cleavage, explain researchers writing in Signal Transduction and Targeted Therapy.

Fu Z, Li S, Han S, et al. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93.

It releases monomethyl auristatin E (MMAE), a molecule that triggers cell cycle arrest and cell death. 

 

Polatuzumab was approved by the FDA in 2019 for use in addition to bendamustine plus rituximab for R/R diffuse large B-cell lymphoma. For this treatment, patients must have received at least two prior therapies.

Fam-trastuzumab deruxtecan-nxki (Enhertu)

Authors of an article in Molecules discuss the ADC fam-trastuzumab deruxtecan-nxki (Enhertu).

Tong JTW, Harris PWR, Brimble MA, et al. An insight into FDA approved antibody-drug conjugates for cancer therapy. Molecules. 2021;26(19):5847.

 

 

To be eligible for treatment, patients must have been administered two or more previous anti-HER2–based regimens.

In 2020, this agent received ADC breakthrough therapy designation for the treatment of patients with metastatic, HER2-mutated, non-small cell lung cancer following a platinum-based therapy. It also received priority review for the treatment of HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma. 

This ADC includes an anti-HER2 antibody, a protease cleavable tetrapeptide-based linker, and a drug payload of DXd.

Sacituzumab govitecan (Trodelvy) 

Sacituzumab govitecan (Trodelvy) consists of an antibody targeting Trop2 conjugated to a topoisomerase I inhibitor (SN-38) via a hydrolysable linker (CL2A). Trop2 is overexpressed in various cancers including breast, cervix, colorectal, esophagus, gastric squamous cell carcinoma of the oral cavity, ovary, pancreas, prostate, stomach, thyroid, urinary bladder, and uterus, as well as certain lung cancers.

Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015 Mar;6(3-4):84-105. doi: 10.18632/genesandcancer.

 

This agent, note the authors of the article in Signal Transduction and Targeted Therapy, received accelerated FDA approval for unresectable locally advanced or metastatic triple-negative breast cancer in patients who have received two or more previous systemic therapies. At least one of these prior therapies had to have been for metastatic disease. 

Cetuximab sarotalocan (Akalux)

The article in Signal Transduction and Targeted Therapy also includes information on cetuximab sarotalocan (Akalux). This ADC consists of cetuximab, an anti-EGFR chimeric monoclonal antibody, conjugated with IRDye 700DX, which is a near-infrared photosensitizing dye. 

 

Dosing of ADCs

 

When dosing ADCs, it is important to keep in mind that these agents fuse the selectivity of an antibody for a specific target with the strength of a small molecule. 

Selection of optimal dosing strategies for ADCs requires careful consideration of the differences between the pharmacokinetics (PK) and pharmacodynamics (PD) of the antibody and the payload. Given that payloads are cytotoxic, a relatively small increase in the systemic exposure of the payload can cause significant adverse reactions.

The FDA explains that the toxicity of the payload is dose limiting from a safety perspective. Therefore, “gaining a thorough understanding of the PK and PD of the ADC and its constituent parts early in development and their relationships to safety and efficacy outcomes is crucial to optimize the ADC dose.”

Authors writing in Drug Safety say that although ADCs are generally well tolerated, common adverse events include infusion-related reactions, ranging from mild allergic reactions to anaphylaxis.

Wolska-Washer A, Robak T. Safety and tolerability of antibody-drug conjugates in cancer. Drug Saf. 2019;42:295–314.

In patients experiencing severe respiratory symptoms, hypotension, or other signs and symptoms of anaphylaxis, discontinuation of the targeted immunotherapy should be considered. As a preventive intervention, approximately 1 hour before infusion, patients can receive premedication with acetaminophen, antihistamines, or corticosteroids.