The Opportunity to go Beyond “Chemo on a Stick” ADCs

Antibodies bearing cytotoxic payloads – though not quite the magic bullets once envisioned – have become a part of late-line therapies for many incurable cancers with at least 15 antibody-drug-conjugates (ADC) approved by the FDA over the last three decades. The landmark approval of gemtuzumab ozogamicin (GO) resulted from decades of research and development in therapeutic antibody generation and engineering, which produced the first-generation ADC with bona fide drug-like characteristics and demonstrated anti-cancer activity in the clinic. GO was the first-ever approved ADC and the first such agent for the treatment of acute myelogenous leukemia (AML). This first-generation conjugate was a humanized murine IgG4 anti-CD33 immunoglobulin covalently linked to the highly potent anti-tumor antibiotic calicheamicin via non-specific lysine coupling through an acid-labile hydrazone linker, achieving a drug antibody ratio (DAR) of 2-3. Though GO induced complete hematologic responses in combination with chemotherapy in patients with refractory or relapsed disease, the agent was not sufficiently active in front-line treatment or as monotherapy.

Moreover, off-target effects due to premature cleavage of the linker in circulation, as well as significant on-target myelotoxicity, drastically curtailed its therapeutic efficacy. Only one other first-generation ADC has received FDA approval (inotuzumab ozogamicin) and both molecules carry a black box warning for increased risk of hepatotoxicity, including severe or fatal hepatic veno-occlusive disease.

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Authors: Ismael Samudio, Ph.D., and David KY Poon, Ph.D ¹

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¹ DCx Biotherapeutics Corporation, Vancouver, Canada