ADAM9 (A disintegrin and metalloprotease 9) is a membrane-anchored protein that is crucial for various physiological functions, mainly through its disintegrin domain for adhesion and metalloprotease domain for ectodomain shedding of cell surface proteins. Its overexpression in various cancers, including pancreatic, esophageal, breast, gastric, lung, and colorectal cancers, is linked to increased tumor aggressiveness and poor prognosis. Although ADAM9 is a promising target for ADC development, its expression in human tissues and immune cells, such as monocytes, macrophages, and neutrophils, poses challenges. This overlapping expression raises the risk of off-target effects and toxicity to normal tissues, which may hinder the efficacy and safety of ADC therapies targeting ADAM9.
Therefore, we have developed an ADAM9 clone, Ab.01, utilizing the fully human RenLite ADAM9 knockout (KO) mice. Ab.01 specifically binds to the membrane-proximal region of ADAM9-L while disregarding the secreted isoform, ADAM9-S. This clone targets ADAM9 without cross-reactivity to other ADAM family members, a specificity confirmed using an ADAM9 KO cell line. Additionally, Ab.01 demonstrated broad binding activity to a panel of cancer cell lines. Ab.01 also showed effective internalization activity. Furthermore, in a PBMC binding assay, Ab.01 demonstrated minimal binding activity to myeloid cells compared to the benchmark antibody. This observation suggests that Ab.01 may reduce off-target interactions, underscoring its potential for improved specificity in therapeutic applications.
Ab.01 conjugated to vcMMAE showed superior efficacy in several PDX models compared to benchmark antibodies conjugated with the same payload. Ab.01 was then conjugated with BLD1102, a novel Top1 inhibitor, resulting in BCG029, which demonstrated potent efficacy in PDX models. Ongoing in vivo studies are continuing to evaluate the performance of BCG029.
These findings underscore the therapeutic potential of BCG029 in targeting solid tumors that express ADAM9. By targeting ADAM9 specifically, BCG029 could provide a safer and more effective treatment option for patients with ADAM9-expressing tumors.
