Preclinical Development of MGC018, a Duocarmycin-based Antibody–drug Conjugate Targeting B7-H3 for Solid Cancer

Abstract

B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer and breast cancer. Over-expression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibodydrug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linkerduocarmycin payload, valine-citrulline-seco duocarmycin hydroxybenzamide azaindole (vcseco-DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa monoclonal antibody through reduced interchain disulfides, with an average drug-to-antibody ratio of ~2.7. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when co-cultured with B7-H3-positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian and lung cancer, as well as melanoma. Additionally, antitumor activity was observed toward patientderived xenograft models of breast, prostate and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers.

B7-H3/CD276: An Emerging Cancer Immunotherapy

“…developed MGC018, an anti-B7-H3 ADC that incorporated an aduocarmycin-based DNA alkylating payload via a cleavable valine–citrulline linker. MGC018 exhibited potent antitumor activity in a range of human tumor xenografts, mediated bystander killing, and showed a favorable safety profile in cynomolgus monkeys ( 80 ).…”

The Role of CD276 in Cancers

“…Significant anti-tumor activity of m276-SL-PBD was observed in PDX models of solid tumors including Ewing sarcoma, rhabdomyosarcoma, Wilms tumors, osteosarcoma, and neuroblastoma. Another anti-CD276 ADC, MGC018 also shows antitumor activity across a range of human tumor xenografts ( 80 ).…”

Surfaceome Profiling of Rhabdomyosarcoma Reveals B7-H3 as a Mediator of Immune Evasion

“…While clinical trials evaluating PD-L1/PD-1 inhibitors in pediatric sarcoma have been unsuccessful, B7-H3 has become a popular target for new, targeted therapies [ 53 ]. Antibody–drug conjugates and CAR-T therapy are currently evaluated in clinical trials and are poised to positively change the therapeutic landscape of childhood cancers [ 54 , 55 , 56 ]. Our work provides novel mechanistic insights into the role of B7-H3 in tumor immune evasion and RMS progression.…”