Precision oncology strategies: The latest in antibody-drug conjugates
Key Takeaways
Anti-drug conjugates (ADCs) consist of a powerful small-molecule drug (the payload) conjugated to an antibody fragment (antibody) by a chemical linker.
The payload should impact only the targeted cell, while exerting minimal effects on non-targeted cells.
When dosing ADCs, the selectivity of an antibody for a specific target, along with the strength of the small molecule, should be considered.
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.[]
Clinical trials for ADCs began in 1980, but were limited by adverse events and lack of efficacy.
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 This specific ADC, however, was voluntarily withdrawn from the market in 2010 due to concerns that adverse events outweighed efficacy.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 As explained in a draft guidance by the FDA, the antibody is engineered against a specific antigen target that exists on the cell surface; this antigen, specific to the disease state being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.[]
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.
Optimally, the payload should interfere with only the targeted cancer cell, while exerting little impact on non-targeted cells. Direct delivery to a specific site means the systemic exposure to the payload can be lower than with delivery via oral or intravenous monotherapy.
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.[] 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).[]
Enhertu received accelerated FDA approval in December 2019 for adult patients with unresectable or metastatic HER2+ breast cancer.
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.[]
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.
This drug is the first anti-Trop2 ADC approved by the FDA for use in metastatic TNBC. It is also approved to treat HR+/HER2- metastatic breast cancer and metastatic urothelial cancer.
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.
Although yet to receive FDA approval, this novel ADC was approved by the Pharmaceuticals and Medical Devices Agency of Japan for unresectable locally advanced or recurrent head and neck squamous cell carcinomas.
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."
— FDA guidance for industry
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.[] 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.
What this means for you
ADCs are emerging as a category of drugs to be reckoned with. Several types have been approved for a variety of cancers during the past few years. Their targeted antibodies and cancer-toxic payload make them precision tools in oncology. Patients should be dosed appropriately and monitored for anaphylactic reactions.