T-Cell(Baylor College of Medicine)

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.”

Invikafusp alfa has recently demonstrated single agent clinical activity across different PD-1 resistant cancers in the ongoing START-001 Phase1/2 clinical study The collaboration plans to evaluate the combination of Marengo's first-in-class TCR Vβ selective dual T cell agonist, STAR0602 (Invikafusp alfa), with Trodelvy (sacituzumab govitecan-hziy) Gilead's Trop-2 directed ADC in a new multi-center Phase I/II clinical study (START-002) Marengo will sponsor the clinical trial and Gilead will provide Trodelvy CAMBRIDGE, Mass., Sept. 13, 2024 /PRNewswire/ -- Marengo Therapeutics, Inc., a clinical-stage biotech company pioneering a new way to activate T cells targeting the Vβ chain of the T cell receptor to select the optimal T cell subsets against cancer, today announced that it has entered into a clinical study collaboration and supply agreement with Gilead Sciences, Inc. to study the combination of STAR0602 (Invikafusp alfa) with Trodelvy® (sacituzumab govitecan-hziy), a Trop-2-directed antibody-drug conjugate (ADC), as a potential treatment for adult patients with metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer and metastatic triple-negative breast cancer (TNBC). The planned combination trial, sponsored by Marengo, is expected to commence soon. This study will evaluate the safety, tolerability, and preliminary efficacy of STAR0602 (Invikafusp alfa) in combination with Trodelvy in patients with metastatic TNBC or metastatic HR+/HER2- breast cancer, aiming to explore a novel therapeutic strategy that could offer new treatment options for patients. "We are excited about the clinical potential of combining our novel selective dual T cell activator with Gilead's antibody-drug conjugate, Trodelvy," said Kevin Chin, M.D., Chief Medical Officer of Marengo Therapeutics. "This innovative approach leverages the strengths of two unique modalities to target and potentially eradicate cancer cells more effectively. With the possibility to deliver target cytotoxic agents directly to tumors, which release more tumor antigens for selectively activated and expanded Vβ6/10 T cells to recognize and build long-term immune memory, we believe this combination may have the potential to improve cancer patient outcomes." Under the clinical study collaboration and supply agreement, Gilead will provide Trodelvy to Marengo, who will conduct and sponsor the combination study. Marengo and Gilead will retain all development and commercial rights to their respective compounds, including as monotherapy or as combination therapies. The combination of invikafusp alfa and sacituzumab govitecan-hziy is investigational and not approved by any health authority globally. The safety and efficacy of this combination has not been established. About Marengo Therapeutics Marengo Therapeutics, Inc, a clinical-stage biotech company, develops novel TCR-targeting antibodies that selectively modulate common and disease-specific T cell subsets of the germline TCR repertoire to provide lifelong protection against cancer and other diseases. With a passionate team of dedicated scientists experienced in immunology and oncology, Marengo's proprietary Selective T Cell Activation Repertoire (STAR) platform leverages an extensive biological understanding of T cell function and receptor signaling to create a world in which everyone's immune system can defeat cancer. To learn more, visit marengotx.com. About STAR™ Platform Marengo's STAR™ Platform is a multi-specific antibody-fusion platform derived from Marengo's proprietary library of antibodies targeting germline-encoded variable (V)β regions of the TCR fused to different T cell co-stimulatory moieties. Combining a novel non-clonal mode of TCR activation with a T cell co-stimulator in the same molecule, promotes a distinct mechanism of action that promotes durable anti-tumor Vβ T cell responses. About STAR0602 STAR0602 is Marengo's lead program, the first T cell activator generated from Marengo's STAR platform; a library of antibodies targeting non-clonal variable (V)β regions of the TCR fused to different co-stimulatory moieties. STAR0602 selectively targets a common Vβ T cell subset present in all cancers and, by combining a novel non-clonal mode of TCR activation with a T cell co-stimulator in the same molecule, promotes expansion of a new population of clonally enriched, effector memory Vβ T cells that turbo-charge tumor immune responses and promote durable clearance of tumors. STAR0602 has undergone extensive preclinical testing, which demonstrates potent anti-tumor activity in both mouse and human ex vivo tumor models attributed to a distinct mechanism of action from existing cancer immunotherapies. About the START-001 Clinical Study START-001 is a Phase 1/2 clinical trial evaluating the safety, tolerability, and preliminary clinical activity of STAR0602 as a single agent in biomarker selected patients with advanced antigen-rich solid tumors including PD-1 refractory and rare tumors. This open-label, multi-center trial consists 2 of two parts: Phase 1 dose escalation and Phase 2 dose expansion. For more information, please visit clinicaltrials.gov (trial identifier: NCT05592626). For patients interested in enrolling in this study at NCI, please contact NCI's toll-free number 1800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615) and/or the website and/or email [email protected] . 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