Three generations of ADC: Nearly a decade of development-PI
Antibody-drug conjugate (ADC), a compound that connects a cytotoxic small-molecule drug to a monoclonal antibody via a rationally established linker, which selectively delivers an efficient cytotoxic agent into the tumor, has made significant progress in the previous decade.
The first ADC drug approved by the US FDA was gemtuzumab ozogamicin (Mylotarg) in 2009. Currently, the FDA has authorized 13 ADC drugs for marketing, with hundreds more in clinical trials.
In 2009, kalimycin, calendula, and medensin analogs were the main cytotoxic agents used for ADC development. Ten years on, these molecules are still being used as payloads for optimization to obtain better stability and hydrophilicity. New cytotoxic substances have also been developed, such as PBDs, duchemicin, and camptothecin derivatives.
Antibody engineering has progressed drastically over the last ten years, allowing for more site-specific coupling and enhancing ADC homogeneity and stability. With the goal of improving therapeutic efficacy and safety, new second and third generation ADCs have entered the clinic. Preclinical investigations have also validated dozens of bioconjugation technologies based on cysteine residues, artificial amino acids, or molecularly engineered models. Furthermore, the development of more tumor-specific antigen targets and mechanisms for intra-tumor cytotoxic drug release have resulted in a surge of ADCs, and ADC drugs have entered a golden era.
First- and second-generation ADCs
Two critical elements determine the success of an ADC drug. The first requires a stable and effective linker that connects the antibody to the payload and remains stable in the plasma circulation while cleaving swiftly after endocytosis in tumor cells to selectively deliver the payload to the tumor while limiting non-targeted toxicity. The linker must be possible to perceive lysosomal conditions (protease, acidic, and reducing media).
The requirement of coupling a potent cytotoxic agent to the antibody is the second crucial criterion for success. Indeed, the initial ADCs had a low therapeutic index due to the low potency of the payload (e.g. anthracyclines), resulting in a still pretty limited therapeutic effect after the maximum tolerated dose (MTD) was reached.
Mylotarg, Besponsa, and first-generation cleavable linkers
In 2000, the FDA authorized Mylotarg for the treatment of acute myeloid leukemia (AML). It consists of a cleavable linker containing a hydrazone bond that connects kacinomycin to gemtuzumab (a mutant anti-CD33 IgG4 subtype monoclonal antibody). The average drug to antibody ratio (DAR) of this ADC is barely 1.5, and it contains roughly 50% uncoupled monoclonal antibodies. The hydrazone bond can be dissolved in the acidic environment of the endosome during ADC internalization, releasing the precursor of kacinomycin, which is then reduced to freely active kacinomycin by glutathione. The latter binds to minor grooves in DNA and undergoes Bergman cyclization, producing a highly reactive double radical that induces sequence-selective DNA double-stranded cleavage.
Hydrazones should stay stable in the circulation at physiological pH and undergo selective hydrolysis following internalization under acidic circumstances, theoretically. However, the linker in Mylotarg was unstable, resulting in the premature release of kacinimycin into the plasma circulation and significant toxicity, prompting Pfizer to pull Mylotarg off the market in 2010.
Thanks to the experience gained in the clinic in recent years and to technological advances, Mylotarg was reapproved in 2017, optimized to improve the stability of the linker, used at lower doses, and with a modified dosing schedule for a different patient population.
A similar linker was developed and used to couple kacinomycin to inotuzumab, a mutant CD22-targeting antibody. Inotuzumab-ozogamicin (Besponsa) was approved by the FDA in 2017 for the treatment of acute lymphoblastic leukemia (ALL).
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