U.S. FDA grants orphan drug designation to ISB 1442 for the treatment of RRMM

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to ISB 1442, a first-in-class anti-CD38/anti-CD47 bispecific antibody, for the treatment of relapsed/refractory (R/R) multiple myeloma (MM).¹

ISB 1442²

ISB 1442 is a biparatopic bispecific antibody with two binding arms to target CD38 and CD47. The CD47 and signal-regulatory protein alpha (SIRPα) interaction is blocked by the anti-CD47 arm, whilst the anti-CD38 arm drives binding with tumor cells and through avidity-induced binding can further block adjacent CD47 receptors. ISB 1442 has an engineered fragment crystallizable region to increase antibody-dependent cell cytotoxicity, antibody-dependent cell phagocytosis, and complement-dependent cytotoxicity. The structure and mechanism of action of ISB 1442 are outlined in Figure 1.

Preclinical data²

In comparison with daratumumab, an anti-CD38 monoclonal antibody, ISB 1442 demonstrated increased antitumor potency in both high and low-CD38-expressing tumors. ISB 1442 showed increased on-target tumor impacts as well as no detectable red blood cell depletion in vitro compared with magrolimab in preclinical trials.

Clinical development

An open-label, first-in-human, multicenter phase I/II study (NCT05427812) will assess the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of ISB 1442 for R/R MM.³ Eligibility criteria include patients with R/R MM who have been treated with a CD38 antibody and have relapsed to three or more prior lines of therapy in the US.³

In this phase I trial, patients will be treated at escalating doses of ISB 1442 to establish its safety profile based on predetermined treatment-related adverse events.² The phase II part of the trial, or dose expansion, will operate in two arms: the first being patients with three prior lines of therapy, including anti-CD38, and the second being patients who have received T cell-redirected therapies.² The phase II primary endpoint is overall response rate. Secondary endpoints include progression-free survival, overall survival, duration of response, pharmacokinetics, and immunogenicity.²