On April 8, 2024 Ichnos Glenmark Innovation (IGI), an alliance between Ichnos Sciences Inc., a global fully-integrated clinical-stage biotech company developing multispecifics in oncology, and Glenmark Pharmaceuticals Ltd., reported preclinical data for its oncology asset ISB 2001 during the oral presentation at the annual American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2024 (Press release, Ichnos Glenmark Innovation, APR 8, 2024, View Source [SID1234641894]). ISB 2001 is currently being tested in a Phase I clinical trial in r/r MM.
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The oral presentation showcased the results of ISB 2001 anti-myeloma activity in bone marrow aspirates from patients who were either newly diagnosed or suffer from r/r MM following multiples lines of treatment, including patients relapsing after CD38 and BCMA targeted therapies. This pre-clinical study shows the promise of ISB 2001 trispecific antibody targeting BCMA and CD38 against multiple myeloma, and CD3 on T cells. It illustrates IGI’s support in the fight against r/r MM.
"We are thrilled to present our preclinical findings for ISB 2001 at AACR (Free AACR Whitepaper)," said Lida Pacaud, MD, Chief Medical Officer of Ichnos Glenmark Innovation. "The development of ISB 2001 holds special significance for us as it is crafted utilizing our cutting-edge BEAT antibody engineering platform, a cornerstone of our pioneering approach to create innovative multispecific treatments for blood cancers and solid tumors."
ISB 2001 – Mechanism of Action
ISB 2001 is the first T cell-engaging antibody that simultaneously targets BCMA and CD38 on MM cells. It is a trispecific antibody based on BEAT (Bispecific Engagement by Antibodies based on the TCR) technology, a proprietary platform allowing maximal flexibility and manufacturability of full length multispecific antibodies. ISB 2001 combines three proprietary antigen-binding arms, each targeting a different antigen, with one arm binding to the epsilon chain of CD3 on T cells, and the other two binding BCMA and CD38 on MM cells. Its fragment crystallizable (Fc) domain was fully silenced to suppress Fc effector functions. ISB 2001 redirects CD3+ T lymphocytes to kill tumor cells expressing low to high levels of both BCMA and CD38. With two different tumor-associated antigens instead of one, ISB 2001 has increased binding specificity to MM cells due to enhanced avidity-based binding.
Other Impactful Preclinical Results
The oral presentation summarized the preclinical characterization of ISB 2001, while focusing on the features that enable ISB 2001 to overcome escape mechanisms.
ISB 2001 showed superior cytotoxicity in comparison with teclistamab, alnuctamab and EM-801 across cell lines with variable expression levels of both BCMA and CD38.
ISB 2001 showed minimal cytotoxicity reduction by soluble factors (sCD38, sBCMA, APRIL) compared to teclistamab, alnuctamab and EM-801, which exhibited cytotoxicity reduction to a much eater degree.
Superior tumor growth inhibition in MM xenograft models relative to teclistamab + daratumumab combination.
Maintained cytotoxicity against MM cell in bone marrow aspirates from two patients relapsing from CD38 or BCMA targeted therapies as well as demonstrated superior cytotoxicity against MM cells over teclistamab in newly diagnosed or r/r patients (as well as smoldering MM and Plasma Cell Leukemia patients).
In relapsed/refractory (r/r) MM patients, who received CD38 targeted therapy, daratumumab cytotoxicity was substantially reduced due to low CD38 expression, while ISB 2001 was still effective.
Teclistamab is considered the next line of treatment in such patients. However, ISB 2001 consistently demonstrated increased cytotoxicity compared to teclistamab in bone marrow aspirates from both newly diagnosed and r/r patients, as well as in two patients with smoldering MM and plasma cell leukemia. Remarkably, ISB 2001 also induced stronger cytotoxic response in one patient relapsing after BCMA targeted therapy, suggesting that the dual targeting by ISB 2001 TCE can overcome the escape mechanisms.
The oral presentation and corresponding data are available for review here. More information about ISB 2001, and the rest of Ichnos’ pipeline can be found here.