ISB-2001

When pitted against Johnson & Johnson's Tecvayli and Bristol Myers Squibb’s candidate alnuctamab in human cell lines, ISB 2001 had a 20-to 260-fold stronger cancer-killing potency. For Ichnos Glenmark Innovation, good things come in threes. The alliance between Ichnos Sciences and Glenmark Pharmaceuticals has developed a trispecific, T-cell activating antibody that shrank multiple myeloma tumors in mice and killed cancer cells in human tissue more effectively than Johnson & Johnson's Tecvayli.The results were published in Nature Cancer on Sept. 11. The drug candidate, ISB 2001, is now in a phase 1 clinical trial.“This is our lead asset, so it's important for us as not only our contribution to the myeloma therapeutic space, but also it's an opportunity to demonstrate the value of our platform,” IGI President and CEO Cyril Konto, M.D., told Fierce Biotech in an interview. That platform, called BEAT (Bispecific Engagement by Antibodies based on the T Cell Receptor), enabled the team to attach binding sites for a T cell surface protein called CD3 onto an antibody heavy chain that also had a binding site for B-cell maturation antigen (BCMA), a known target on multiple myeloma cancer cells. The other heavy chain of the vaguely Y-shaped antibody targets CD38, another myeloma target.Binding to all three targets brings the T cell and the tumor together, Konto said. From there, the T cells can attack and kill the cancerous cells.When pitted against bispecifics such as Janssen's Tecvayli and Bristol Myers Squibb’s candidate alnuctamab in human cell lines, ISB 2001 had a 20-to 260-fold stronger cancer-killing potency. The trispecific also beat Tecvayli at killing tumors taken from multiple myeloma patients.To further test ISB 2001’s cancer-killing prowess, the researchers grafted human myeloma tumor cells onto mice and treated them with the antibodies. At a 0.1-mg/kg dose, ISB 2001 completely eradicated the tumors of all eight mice; Tecvayli, meanwhile, had no complete regressions and showed 30.8% tumor growth inhibition.T-cell activators like ISB 2001 run the risk of over-activating the immune cells and sparking cascades of inflammatory cytokines.“Often, greater potency comes at the cost of more side effects,” Sigrid Ruuls, Ph.D., and Paul Parren, Ph.D., wrote in a Nature Cancer commentary piece on the new study. “Even though ISB 2001 showed greater T cell-mediated cytotoxicity of tumor cells than that of teclistamab and another control CD3xBCMA bispecific, T cell cytokine secretion was not higher. Thus, there could be a larger therapeutic window for ISB 2001 than for other TCEs.” Ichnos has enrolled about 20 patients in the phase 1 trial so far, Konto said, and the company hopes to present preliminary data in multiple myeloma patients at a conference later this year.Glenmark, a multinational company with headquarters in India, is the sole backer of IGI. Ichnos was originally spun out of Glenmark in 2019.IGI has another antibody, a bispecific called ISB 1442, currently in a phase 1/2 trial for relapsed or refractory multiple myeloma. And a small molecule from the Glenmark side of the collaboration targets the T-cell regulator CBL-B, which Konto said could potentially be used in combination with ISB 2001 down the line if all goes well.“We're bringing the T cell and the tumor all together, and with a small molecule, we could improve the potency of the T cells themselves,” Konto said. “On paper, it looks great.”

Article highlights preclinical findings demonstrating ISB 2001 can potentially overcome myeloma cell escape mechanisms to evade therapeutic anti-tumor activityData show superior killing potency of multiple myeloma tumor cells by ISB 2001 when compared to several approved bispecific therapies and combination of therapies NEW YORK, Sept. 11, 2024 (GLOBE NEWSWIRE) -- 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., announced today that Nature Cancer published a research article describing the preclinical development of ISB 2001, a first-in-class trispecific antibody targeting BCMA and CD38 on myeloma cells and CD3 on T cells. ISB 2001 is currently being investigated in a Phase 1 clinical study in relapsed/refractory multiple myeloma (r/r MM). “Despite advances with monoclonal antibodies and earlier-generation bispecifics, a high relapse rate and resistance to currently available therapeutics are persistent challenges in treating multiple myeloma," said Cyril Konto, M.D., President, Executive Director and CEO of IGI. “The publication of ISB 2001 preclinical data in Nature Cancer supports the differentiation and mechanism of action of IGI’s multispecific antibody. These comprehensive findings underscore the therapeutic potential of ISB 2001, now in Phase 1 clinical testing, and we look forward to sharing our continued progress.” Key findings of the Nature Cancer article, “ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells” include the following: The data demonstrate that ISB 2001 can overcome resistance mechanisms by dual tumor targeting via binding and cytotoxicity of tumor cells with low expression of CD38 or BCMA.ISB 2001’s architecture is optimized to support robust killing of tumor cells while limiting CD38 on-target, off-tumor activity.ISB 2001 demonstrated increased killing of tumor cells compared to BCMA-targeted T cell engagers in vitro, in vivo and ex vivo; induced complete tumor regression in humanized mouse models; and demonstrated superior potency compared to standard combination of therapies. “We leveraged our proprietary BEAT® platform to create a highly specific antibody that increases binding to MM cells while minimizing off-target activity,” said Mario Perro, Ph.D., Head of Biologics Research at IGI. “These preclinical data demonstrate the potential of a trispecific approach to augment immune cell activation and achieve more precise tumor targeting and killing.” The paper can be found at https://www-nature-com.libproxy1.nus.edu.sg/articles/s43018-024-00821-1. ISB 2001 – Mechanism of ActionISB 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 BCMA and CD38. Targeting of two different tumor-associated antigens instead of one allows for avidity binding to MM cells expressing very low levels of BCMA and CD38. About Ichnos Glenmark Innovation Ichnos Glenmark Innovation (IGI) is an alliance between Ichnos Sciences Inc., a global fully-integrated clinical-stage biotech company developing multispecifics™ in oncology, and Glenmark Pharmaceuticals Ltd. (Glenmark), with the aim to accelerate new drug discovery in cancer treatment. IGI combines Ichnos' research and development proficiencies in novel biologics with those of Glenmark’s in new small molecules to continue developing cutting-edge therapy solutions that treat hematological malignancies and solid tumors. Harnessing the combined proficiency of over 150 scientists and a robust pipeline of novel molecules, this collaboration will leverage the capabilities of its three global centers of innovation spread across the USA, Switzerland and India to propel Innovation. For more information, visit www.iginnovate.com. For more information, please contact:IGI Corporate Communications Team Corporate.communications@iginnovate.com