Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma
Authors: Dhakal Binod , Quach Hang , Ho Phoebe Joy , Spencer Andrew , Schroeder Mark A. , Tan Peter , Cochrane Tara , Sia Hanlon , Zonder Jeffrey A. , Martinet Camille , Duchesne Dominique , Garton Andrew , Menon Vinu , Holkova Beata , Konto Cyril , Pacaud Lida , Kazandjian Dickran 
Published: December 2024

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody targeting CD38 and CD47, generated using Ichnos' Bispecific Engagement by Antibodies based on the T cell receptor (BEAT®) platform for treatment of relapsed/refractory multiple myeloma (RRMM). It combines two anti-CD38 binding arms with a single anti-CD47 arm to harness innate immunity and enhance tumor cell killing through multiple mechanisms: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. We report here results from the dose-escalation portion of an ongoing phase 1/2 study.
Methods: Trial enrolled pts with RRMM previously exposed to at least 3 prior lines, including proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies. ISB 1442 was given subcutaneously (SC) weekly (QW) in 28-day cycles. Dose escalation began at 6 mg dose with an accelerated titration (single pt) for the first 3 cohorts, followed by a standard “3 + 3” design if pre-defined conversion criteria were met. The primary objective was safety and tolerability to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).
Results: As of July 25th, 2024, 26 pts received ISB 1442 in 6 dose-groups from 6 mg to 450 mg fixed doses. The median age was 69y (range 45 to 82), 58% were male and 81% white. The median number of prior lines was 6 (range 2 to 12); all 26 pts were triple-class exposed, 21/26 were penta-drug exposed (6/12 penta-drug refractory). The median number of cycles was 2 (range 1 to 5). 24 pts (92.3%) experienced treatment-related adverse events (TRAEs), 46.1% had grade 3 and higher: anemia (26.9%), neutropenia (15.4%), thrombocytopenia (26.9%). No grade 5 TRAE was observed. AEs of special interest were cytokine release syndrome (CRS) (34.6%, all grade 1 or 2), injection site reactions (3.8%, all grade 1), hemolysis (3.8%, all grade 1) and pyrexia (3.8%, all grade 1). Due to occurrence of CRS at 150 mg (88.9%), as pre-specified, a priming dose (60 mg on C1D1) was introduced for subsequent cohorts. CRS incidence decreased after introduction of priming. Median time to CRS was 1 day (range 1 to 22), with a median duration of 2 days (range 1 to 5). Tocilizumab was used in 5 pts.
To date, 2 of the 4 pts treated at 450 mg had dose-limiting Grade 4 thrombocytopenia. Safety mitigation steps were added to resume enrollment. Best response to date is stable disease (SD) in 8 out of 26 response evaluable pts (median duration 29 days, range: 1 to 99).
ISB 1442 was slowly absorbed into the circulation with Tmax generally 2 to 4 days post dosing. PK data up to 450 mg suggest super-proportional increase in serum levels. The sharp decline in serum profile after Cmax suggest target mediated drug disposition (TMDD) predominantly driven by blood compartment rather than bone marrow, implying higher dose levels may be needed to achieve required efficacy concentrations in bone marrow.
Assessment of 63 soluble factors (cytokines, chemokines and growth factors) in the peripheral blood revealed pattern of transient increases of 15 analytes following the initial administrations of ISB 1442 at dose levels of 60 mg and above. Changes in these analytes were associated with the severity of CRS, and included several biomarkers that are potentially related to the proposed macrophage-driven mechanism of action of ISB 1442. Receptor occupancy by flow cytometry indicated that higher doses were associated with an increasing saturation of ISB 1442 binding sites on multiple CD38-expressing cell types in the peripheral blood. Saturation appeared to approach 100% in some samples but limited anti-tumor activity has been observed to date, suggesting that higher dose levels, leading to prolonged saturation of ISB 1442 binding on the bone marrow multiple myeloma cells through the dosing period, may be required for optimal clinical efficacy.
Conclusion:Treatment with ISB 1442 is associated with manageable toxicity. The observed clinical CRS events were moderate (Grade 1 and 2) and potentially related to macrophage activation following ISB 1442 administration. Super-proportional PK and receptor occupancy biomarkers suggest higher dose levels may be needed to achieve required efficacy concentrations in bone marrow compartment. The study continues to enroll in the dose escalation (NCT05427812).