Harnessing the Power of ISB 1442: A Pioneering Approach to Targeting CD38 and CD47 in Relapsed Refractory Multiple Myeloma

ISB 1442 is a unique bispecific antibody designed to treat relapsed/refractory multiple myeloma (rrMM). It features two binding sites targeting CD38 and one for CD47, leveraging a proprietary platform that enhances T-cell receptor engagement. This fully human antibody is engineered to strongly bind to CD38 via bi-paratopic Fabs and to block CD47's interaction with phagocyte receptors, such as SIRPα, with a single Fab arm. This configuration allows ISB 1442 to preferentially bind to tumor cells and block proximal CD47 receptors, potentially reducing unintended effects on red blood cells compared to standard anti-CD47 antibodies like magrolimab.

The Fc region of ISB 1442 has been optimized to boost antibody-dependent cell phagocytosis (ADCP), cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC), marking it as a first-in-class candidate with these attributes. It is intended to counteract resistance mechanisms to daratumumab, a common treatment for rrMM.

In vitro studies revealed that ISB 1442 is more potent than daratumumab in eliminating a wide range of CD38-expressing tumor cells. It demonstrated high efficacy against CD38-high cells through CDC and superior efficacy against CD38-low cells via ADCC and ADCP. Moreover, ISB 1442 matched the phagocytic killing potency of magrolimab, an anti-CD47 monoclonal antibody, and induced more potent CDC and ADCC killing of tumor cells due to its functional Fc region.

A novel in vitro assay, termed MMoAK, was developed to assess the multifaceted action of ISB 1442, utilizing macrophages and peripheral blood mononuclear cells (PBMCs) from donors alongside tumor cells and human serum. This system showed that ISB 1442 could target tumor cells through NK cells, macrophages, and serum complement, resulting in significantly higher tumor cell killing than daratumumab.

The design of ISB 1442 was shown to mitigate the risk of antigen sink effects from CD47 and CD38, as evidenced by its lack of impact from soluble CD38 or red blood cells in vitro assays. Furthermore, ISB 1442 displayed a favorable on-target specificity profile, with no detectable hemolysis, red blood cell depletion, or platelet aggregation, and significantly reduced hemagglutination compared to magrolimab.

In an in vivo model using Raji tumor xenograft in CB17/SCID mice, ISB 1442 demonstrated enhanced tumor growth inhibition compared to daratumumab and comparable tumor regression to magrolimab.

In conclusion, the innovative design of ISB 1442, which co-targets CD38 and CD47 with a 2+1 biparatopic format, is expected to improve antitumor activity in rrMM patients by overcoming primary and acquired resistance mechanisms.