Calicheamicin Antibody-Drug Conjugates with Improved Properties.

Area of Science:

• Bioconjugation Chemistry
• Antibody-Drug Conjugates (ADCs)
• Cancer Therapeutics

Background:

• Existing calicheamicin antibody-drug conjugates (ADCs) face challenges with heterogeneity, aggregation, and short half-lives due to unstable linkers.
• Approved calicheamicin ADCs like Mylotarg and Besponsa target CD33 and CD22, respectively, for hematologic malignancies.

Purpose of the Study:

• To develop improved calicheamicin ADCs with enhanced stability, reduced aggregation, and better circulation half-life.
• To create homogeneous, site-specific conjugates using a novel linkerless approach.

Main Methods:

• Direct attachment of reduced calicheamicin to engineered antibody cysteines via a disulfide bond, creating a linkerless conjugate.
• Evaluation of conjugate homogeneity, aggregation, in vivo stability, efficacy in solid and hematologic tumor models, and safety in preclinical studies.

Main Results:

• Generated homogeneous calicheamicin ADCs with minimal aggregation and high in vivo stability (50% drug conjugated after 21 days).
• Demonstrated high efficacy in mouse models of HER2+ breast cancer and CD22+ non-Hodgkin lymphoma.
• Observed increased tolerability in rat safety studies compared to Mylotarg.

Conclusions:

• Novel linker chemistry and site-specific conjugation yield improved, next-generation calicheamicin ADCs.
• The linkerless approach overcomes limitations of previous calicheamicin ADCs, offering enhanced therapeutic potential.