Calicheamicin is a member of the enediyne antitumor antibiotics, a class of extremely potent natural-product cytotoxins. Calicheamicin binds to the minor groove of DNA, where intracellular thiols activate the enediyne core, causing double-strand DNA breaks via a Bergman cyclization reaction, ultimately leading to apoptosis.
Due to its highly effective killing mechanism, Calicheamicin remains a “gold standard” payload for targeted delivery. However, it is also extremely hydrophobic and challenging to work with.
Gemtuzumab ozogamicin (marketed by Pfizer) is the first FDA-approved ADC for acute myeloid leukemia (AML) using Calicheamicin as its payload. It was first approved in 2000, later withdrawn, and subsequently re-approved by the FDA in 2017 for newly diagnosed and relapsed/refractory CD33-positive AML in adults and children. The drug is non-specifically conjugated via surface amine groups on the antibody and employs a cleavable hydrazone linkage together with a disulfide bond, achieving an average DAR of 2–3.
Inotuzumab ozogamicin, also marketed by Pfizer, was approved by the FDA in 2017 for relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL). It utilizes the same conjugation chemistry and linker design as Gemtuzumab ozogamicin, with an average DAR of approximately 6.
The AqT®-Calicheamicin (CM81307) drug asset is currently available for partner evaluation, using site-specific reduced-thiol labeling chemistry with a releasable linker. This design enables efficient loading of four to six drug molecules per antibody with minimal aggregation or precipitation.