Placental (ALPP) and germ cell (ALPG) alkaline phosphatases, sharing 98% sequence homology, are tumor-associated antigens with a highly restricted expression profile. While largely absent in normal adult tissues, they are frequently overexpressed across a wide spectrum of malignancies, including pancreatic, gastric, ovarian, and lung cancers. Elevated ALPP/ALPG levels correlate with poor prognosis in gastric and ovarian cancers, making them compelling targets for antibody-based therapies.
Here, we report the development of BCG037, a first-in-class, fully human IgG1 antibody-drug conjugate (ADC) targeting ALPP/ALPG. The antibody was generated from RenMab™ humanized mice and conjugated with the potent topoisomerase I (Top1) inhibitor payload, achieving a high drug-to-antibody ratio (DAR) of ~8.
BCG037 exhibits high affinity (nanomolar range) and cross-reactivity to both human and cynomolgus monkey ALPP/ALPG, with no cross-reactivity to other ALP family members (ALPL, ALPI). Notably, the antibody component of BCG037 demonstrates superior binding affinity to tumor cells compared to the analog used in SGN-ALPV. In vivo, BCG037 treatment led to significant and superior tumor growth inhibition in both pancreatic and gastric cancer patient-derived xenograft (PDX) models, outperforming the benchmark ADC, SGN-ALPV-MMAE, and no treatment-related toxicity or weight loss was observed in mice.
Collectively, these data validate ALPP/ALPG as promising therapeutic targets and position BCG037 as a highly novel and potent clinical candidate for treating ALPP/ALPG-positive malignancies, including refractory cancers with limited treatment options.
