ABSTRACT
Introduction: Antibody-Drug Conjugates (ADCs) have undergone a recent resurgence with 5 product approvals over the last 2 years but for those close to the field, it’s been repeated cycles of setbacks and new innovations. A new wave of innovation is in the type of format used to deliver the cytotoxic payloads, with smaller bio-molecules being designed to have more optimal penetration and elimination properties tailored for solid tumors.
Areas covered: In this review, the authors cover many of the recently described smaller-format drug conjugates (including formats such as diabodies, Fabs, scFvs, domain antibodies) with an emphasis on the types of conjugation technologies used to attach the chemical linker-payload.
Expert opinion: Smaller formats are highly influenced by the structure of the linker-payload, arguably more-so than larger ADCs, so careful consideration is needed where solublising and pharmacokinetic modulation is required. High-quality conjugates are being developed with in vivo tumor efficacy and tolerability properties competitive with ADCs and with a few formats already in clinical development, we expect the pipeline to expand and to reach the market.
Article highlights
Many differently-sized formats have been described with varying degrees of success
A variety of chemical conjugation strategies exist, dominated by thiol conjugation
Half-life extension is critical for smaller, non-Fc formats to be viable, achieved by the incorporation of albumin binding domains or hydrophilic polymers
Smaller, peptidic-drug conjugates are more clinically advanced and demonstrating efficacy and good tolerability in patients
The area is still dominated by the larger ADCs but more of these novel formats will advance into the clinic.
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Declaration of interest
Both authors are employees of Antikor BioPharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.