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73 ISB 1442, a First-in-Class CD38 and CD47 Bispecific Antibody Innate Cell Modulator for the Treatment of Relapsed Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational I
Hematology Disease Topics & Pathways:
Translational Research
Saturday, December 11, 2021: 9:45 AM

Sammicheli Stefano, PhD1*, Camille Grandclement, PhD1*, Elie Dehilly, PhD1*, Maria Panagopoulou, PhD1*, Evangelia Martini1*, Rosa Castillo1*, Perrine Suere1*, Blandine Pouleau1*, Carole Estoppey, PhD1*, Julia Frei, PhD1*, Jeremy Loyau, PhD1*, Thierry Monney, PhD1*, Rebecca Wood, PhD1*, Amelie Croset, PhD1*, Alain Rubod1*, Girish Gudi, PhD2*, Venkatesha Udupa, DVM, MVSc, PhD, DABT, ERT, DSP3*, Sunitha Gn, PhD3*, Vinu Menon, PhD4*, Daniel Rasmussen, PhD5*, Jeppe Koch Olsen, PhD6*, Roberto Giovannini, PhD5*, Aravind Chakrapani, PhD1*, Stanislas Blein, PhD1*, Marie-Agnes Doucey, PhD1*, Adam Drake, PhD1*, Alessandro Riva, MD7*, Cyril Konto, MD7, Mario Perro, PhD1* and Lamine Mbow, PhD1*

1Ichnos Sciences, Epalinges, Switzerland
2Ichnos Sciences, New York, NY
3Glenmark Pharmaceuticals Limited, Mahape, India
4Glenmark Pharmaceuticals Limited, Mumbai, India
5Ichnos Sciences, La Chaux-de-Fonds, Switzerland
6Chemin de la Combeta 5, Ichnos Sciences SA, La Chaux-de-Fonds, Switzerland
7Ichnos Sciences, New York

ISB 1442 is a bispecific antibody (BsAb) using Ichnos' proprietary Bispecific Engagement by Antibodies based on the T-cell receptor (BEAT®) platform. A fully human BsAb with anti-CD38 and CD47 binding arms, ISB 1442 was developed for the treatment of relapsed/refractory multiple myeloma (rrMM). The CD38 binding arm consists of two bi-paratopic Fabs that strongly bind to CD38 through avidity-induced interactions. The anti-CD47 arm comprises a single Fab arm designed to block the interaction between CD47 and the signal-regulatory protein alpha (SIRPα) receptor present on phagocytes (including macrophages, monocytes and dendritic cells). With this design, the CD38 Fab arm preferentially drives binding to tumor cells and enables blocking of proximal CD47 receptors on the same cell via avidity-induced binding. Hence, ISB 1442 is anticipated to induce minimal unintended effects on red blood cell (RBC) hemagglutination compared to benchmark anti-CD47 monoclonal antibodies (mAb) magrolimab. The Fc portion of ISB 1442 is engineered to enhance antibody dependent cell phagocytosis (ADCP), antibody dependent cell cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). ISB 1442 is the first-in-class with these unique molecular attributes, which are designed to overcome mechanisms of resistance to daratumumab in rrMM patients.

In vitro, ISB 1442 exhibited a higher killing potency compared to benchmark daratumumab across a broad range of CD38-expressing tumor cells. Specifically, ISB 1442 showed a high potency to kill CD38high tumor cells through CDC and a superior potency to kill CD38low expressing tumor cells through ADCC and ADCP compared to daratumumab. Additionally, ISB 1442 showed in vitro tumor killing potency through phagocytosis comparable to magrolimab, an anti-CD47 mAb (IgG4) acting mostly through ADCP. Consistent with its molecular design, which includes a functional Fc, ISB 1442 induced more potent killing of CD38high and CD38low tumor cells by CDC and ADCC compared to magrolimab. To characterize the complex mechanisms of action of ISB 1442 in a single system more fully, a multiple mode of action of killing (MMoAK) in vitro assay was established where autologous macrophages and PBMCs from healthy donors were incubated with CD38low expressing tumor cells and human serum. With this approach, tumor cells can be targeted simultaneously by NK cells from PBMCs, autologous macrophages, and complement from human serum. In MMoAK, ISB 1442 exhibited prominent tumor cell killing that was twice as high as daratumumab. The presence of soluble CD38 or RBCs, the main source of antigen sinks for CD38 and CD47, did not affect the killing potency of ISB 1442 across in vitro assays using CD38high or CD38low expressing tumor cells. These data suggest that the molecular design of ISB 1442 mitigates the potential risk of CD47 and CD38 antigen sink and the related side effects.

On-target specificity was evaluated in vitro by measuring binding to human RBCs, induction of hemagglutination and RBC depletion, hemolysis and platelet aggregation. ISB 1442 did not cause any detectable hemolysis, RBC depletion or platelet aggregation in vitro and showed a marked reduction in human RBC hemagglutination relative to magrolimab, suggesting a more favorable on-target specificity profile.

Finally, the potency of ISB 1442 was assessed in vivo in a therapeutic model of subcutaneously established Raji tumor xenograft in CB17/SCID mice which have functional complement, macrophages and NK cells of murine origin. ISB 1442 induced higher tumor growth inhibition relative to daratumumab and comparable tumor regression compared to magrolimab.

In summary, we report a novel approach for the treatment for rrMM by co-targeting CD38 and CD47 using a 2+1 biparatopic bispecific antibody. Based on its unique design and multiple mechanisms of action, ISB 1442 is anticipated to enhance antitumor activity in rrMM patients relative to anti-CD38 mAbs by overcoming primary and acquired tumor escape mechanisms of resistance.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH