Unique Properties of ISB 2001 May Offer Benefits in R/R Multiple Myeloma

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, CancerNetwork® spoke with Hang Quach, MBBS, MD, FRACP, FRCPA, about the properties that may make ISB 2001, a first-in-class trispecific T-cell engager, stand out from other therapies for relapsed/refractory multiple myeloma. She spoke in the context of findings from a first-in-human phase 1 study (NCT05862012) assessing ISB 2001 for this patient population during a rapid oral abstract session at the meeting.

Quach, a professor of hematology at the University of Melbourne and head of the Department of Clinical Hematology and Clinical Hematology Research at St Vincent’s Hospital Melbourne in Australia, stated that the ability of ISB 2001 to bind to CD38 and BCMA with high affinity may facilitate T-cell–mediated cytotoxicity even in the event of downregulation, thereby overcoming resistance observed with other BCMA-targeted agents. Additionally, the agent’s ability to bind to CD3 with low affinity may limit off-tumor T-cell–mediated toxicity. Quach concluded by describing how the responses observed with ISB 2001 in the phase 1 trial may pave the way for future combinational strategies with other anti-CD38 monoclonal antibodies.

Transcript:

[What] makes ISB 2001 unique and distinctly different from other traditional bispecific antibodies is, firstly, the dual and high-affinity binding to CD38 and BCMA. This dual high-affinity binding allows for T-cell–mediated cytotoxicity even upon downregulation of BCMA or CD38, which is quite a common resistance mechanism that we see with other BCMA-targeted agents.

Secondly, the weak binding to CD3, or the low-affinity binding to CD3, allows for less off-tumor T-cell–mediated toxicity. In addition, it also reduces the risk of T-cell absorption that we may see with resistance. One more unique aspect is the fact that the CD38-binding epitope of ISB 2001 is distinct from that of a daratumumab [Darzalex] or isatuximab-irfc [Sarclisa], and this is the reason why we see people progressing on anti-CD38 monoclonal antibodies within 6 months still respond just as well, if not a little bit better, than what we see with the overall patient population. Their overall response rates were in the order of higher than 80%. That’s quite remarkable, and it does pave the way for synergism if ISB 2001 is combined with anti-CD38 monoclonal antibodies down the track.

Reference

Lichtman E, Khot A, Augustson B, et al. Phase 1, first-in-human study of ISB 2001: a BCMAxCD38xCD3-targeting trispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—dose escalation (DE) results. J Clin Oncol. 2025;43(suppl 16):7514. doi:10.1200/JCO.2025.43.16_suppl.7514