Advancements in Multiple Myeloma Therapy: The Emergence of STI-6129 as a Promising Anti-CD38 ADC

CD38 is a well-established target for treating hematologic malignancies like multiple myeloma (MM), with daratumumab being a frontline anti-CD38 monoclonal antibody (mAb). However, resistance to daratumumab poses a significant challenge. The preclinical development of STI-6129, a novel CD38-targeting antibody-drug conjugate (ADC), is being explored as a therapeutic for MM.

STI-6129 is composed of a fully human anti-CD38 antibody, STI-5171, linked to the microtubule inhibitor duostatin-5.2 (Duo-5.2) using site-specific C-LOCK technology. The antibody STI-5171 selectively binds to CD38-positive tumor cells with high affinity. STI-6129 is internalized by CD38-positive cells and has demonstrated cytotoxic activity against a range of CD38-expressing tumor cell lines without affecting normal human peripheral blood mononuclear cells (PBMCs).

The mechanism of action of STI-5171 differs from daratumumab in that it does not induce homotypic aggregation of tumor cells, a response associated with drug resistance and increased metastatic potential. STI-6129 has shown broad and potent in vivo anti-tumor efficacy in various xenograft models. Pharmacokinetic studies in Daudi-Fluc tumor-bearing mice indicate that the ADC is stable with a half-life of 7-11 days, similar to the unconjugated antibody. A single injection of STI-6129 at 10 mg/kg maintained a therapeutic serum concentration for up to a week. In cynomolgus monkeys, the PK profiles of STI-6129 and STI-5171 were nearly identical, confirming the ADC's stability in circulation.

In conclusion, STI-6129 has exhibited significant in vitro and in vivo anti-tumor activities against CD38-positive hematological models. These findings suggest the potential of STI-6129 as a promising therapeutic agent for the treatment of multiple myeloma, possibly serving as a superior or alternative option to existing treatments.