On October 4, 2023 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported the National Institutes of Health (NIH) awarded Actinium a Small Business Technology Transfer grant extension to support its clinical collaboration with Memorial Sloan Kettering Cancer Center (MSK) to study Iomab-ACT, Actinium’s CD45-targeting radiotherapeutic, for targeted conditioning to achieve lymphodepletion therapy along with the reduction of cytokine release syndrome and neurotoxicity prior to administration of a CD19-targeted CAR-T cell therapy developed at MSK (Press release, Actinium Pharmaceuticals, OCT 4, 2023, View Source [SID1234635632]).

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"Iomab-ACT has the potential to significantly improve the patient journey and increase patient access to revolutionary therapies like cellular and gene therapies by eliminating or reducing the need for non-targeted chemotherapy," said Sandesh Seth, Chairman and Chief Executive Officer. "We are grateful to have been awarded the extension of this NIH grant, which will fund the advancement of this important clinical collaboration."

Iomab-ACT is a next-generation, CD45-targeted conditioning agent intended to enable either lymphodepletion or reduced intensity conditioning prior to CAR-T and gene therapies with multi-indication potential. Iomab-ACT has the potential to reduce toxicities and improve patient outcomes when paired with MSK’s CD19 CAR-T cell therapy in difficult to treat relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B cell lymphoma (DLBCL). This grant will advance the ongoing study of Iomab-ACT for patients with relapsed or refractory B-ALL or DLBCL.

On October 4, 2023 AbbVie (NYSE: ABBV), the Broad Institute of MIT and Harvard, and Calico Life Sciences reported the publication in Nature of the discovery and preclinical data that demonstrate investigational ABBV-CLS-484 is a potential first-in-class, orally bioavailable, PTPN2/N1 phosphatase inhibitor that enhances anti-tumor immunity (Press release, AbbVie, OCT 4, 2023, View Source [SID1234635631]). The findings, based on research conducted by AbbVie in collaboration with the Broad Institute and Calico, support the development of ABBV-CLS-484 as a promising new strategy for cancer immunotherapy.

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Titled "The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity," the paper highlights the novel structural insights and design that led to the discovery of ABBV-CLS-484 and its dual mechanism of action that targets tumor cells and suppresses their growth, as well as promotes the activation of several immune cell types to increase their anti-tumor activity.1

Researchers at the Broad previously identified protein tyrosine phosphatase non-receptor type 2 (PTPN2) and its closely related paralog PTPN1 as potential targets for cancer immunotherapy through an in vivo CRISPR screen.2 However, this challenging target class had previously been deemed "undruggable". AbbVie researchers overcame the challenges and discovered the dual PTPN2/N1 inhibitor, ABBV-CLS-484, through structure-based drug design and optimization of drug-like properties.

Discovery scientists at AbbVie, the Broad, and Calico further uncovered the biology and mechanism of action of ABBV-CLS-484. Preclinical findings presented demonstrate that ABBV-CLS-484 treatment amplifies the tumor intrinsic response to interferon and increases the activation and function of several immune cell subsets promoting cellular pathways including JAK-STAT signaling in animal models. In murine cancer models resistant to PD-1 blockade, monotherapy ABBV-CLS-484 treatment generates robust anti-tumor immunity. Through in vivo studies and single cell transcriptional profiling of tumor-infiltrating lymphocytes from ABBV-CLS-484 treated mice, the team revealed that ABBV-CLS-484 inflames the tumor microenvironment and promotes NK and CD8+ T-cell function. In T cells, mechanistically, ABBV-CLS-484 induces epigenetic and metabolic changes resulting in a unique functional state causing increased cytotoxicity and reduced T-cell exhaustion and dysfunction.

"Immunotherapies like PD-1 blockade have revolutionized cancer treatment; however, many patients do not respond well to them, and a significant unmet need remains," said Christina Baumgartner, Ph.D., co-first author and senior principal research scientist, AbbVie. "Through the extraordinary efforts of AbbVie’s medicinal chemistry team to drug the undruggable, we now have a potential first-in-class PTPN2/N1 inhibitor. We’re excited to share its biology and mechanism of action, and look forward to further evaluating it in the clinic."

"This study is a powerful demonstration of how collaboration can bring together diverse expertise to advance our understanding of disease biology and lead to discoveries that support new treatment strategies for people living with cancer," said Marcia Paddock, M.D., Ph.D., co-author and director of oncology new target development at Calico. "We are proud to be working with both AbbVie and the Broad Institute and look forward to sharing additional progress from our clinical studies of this novel immunotherapy."

ABBV-CLS-484 is the first active-site phosphatase inhibitor to enter clinical evaluation as a cancer therapy and is currently in an AbbVie and Calico-led Phase 1 clinical trial in solid tumors (NCT04777994).

"This is an unprecedented opportunity to evaluate how immune responses work," said Robert Manguso, Ph.D., co-senior author on the study, associate member at the Broad, and assistant professor at the Massachusetts General Hospital Center for Cancer Research and Harvard Medical School. "The ability to further explore this signaling pathway in clinical studies is really important."

On October 3, 2023 Oxford BioTherapeutics (OBT), a clinical stage oncology company with a pipeline of immuno-oncology and Antibody Drug Conjugate (ADC)-based therapies, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to BI 764532 for the treatment of extensive stage small cell lung cancer (ES-SCLC) whose disease has progressed following at least two prior lines of treatment including platinum-based chemotherapy, and of advanced or metastatic extrapulmonary neuroendocrine carcinomas (epNEC) whose disease has progressed following at least one prior line of treatment including platinum-based chemotherapy (Press release, Oxford BioTherapeutics, OCT 3, 2023, View Source [SID1234656435]).

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BI 764532 is an investigational DLL3/CD3 IgG-like T-cell engager for treatment of patients with SCLC and other neuroendocrine tumors that is being developed by Boehringer Ingelheim. The discovery of BI 764532 was enabled through a successful partnership initiated in 2013, leveraging OBT’s proprietary OGAP drug discovery platform for identification of the DLL3 antigen and Boehringer Ingelheim’s longstanding expertise in oncology and development of biotherapeutics.

Encouraging data were presented from the Phase I first-in-human dose-escalation trial at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2023 Annual Meeting. These Phase I data demonstrated a clinically acceptable safety profile and early efficacy in patients with DLL3-positive ES-SCLC and epNECs.

Christian Rohlff, Chief Executive Officer of OBT, commented: "We are delighted about the accelerated clinical development of BI 764532, for which the DLL3 antigen was discovered using our OGAP technology platform. This is tremendously exciting for OBT, as it shows the real impact this partnership has for patients in need. Receiving an ES-SCLC or epNEC diagnosis can be life changing and there is an urgent, unmet need for additional targeted immunotherapeutics to ensure that individuals impacted by these aggressive cancers get the care they need."

FDA’s Fast Track designation is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening diseases and that demonstrate the potential to address unmet medical needs.

On October 3, 2023 Pacylex Pharmaceuticals, a clinical stage pharmaceutical company focused on the development of therapies for hematologic and solid cancers, reported recent results generated at NIH using its lead drug, zelenirstat, presented at the Canadian Association of Radiation Oncology Annual Meeting in Montreal, Canada, on September 23, 2023 (Press release, Pacylex Pharmaceuticals, OCT 3, 2023, View Source [SID1234645056]).

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The presentation, titled "Radiosensitization with Glioblastoma using Targeted Inhibition of N-Myristoylation" highlighted that:

Zelenirstat was more effective than clinically used radiosensitizers, which generally augment the effects of radiation by 10% to 30%, increasing the effects of radiation by 40% – 140%;
Orally administered zelenirstat is also predicted to cross the blood brain barrier more efficiently than temozolomide, the current standard of care radiosensitizer for aggressive brain cancers.
Dr. Deepak Dinakaran, MD, PhD, a radiation oncologist and clinician scientist who conducted this research at the US National Institute of Health, said, "Our results show that zelenirstat is a potent radiosensitizer in preclinical models of glioblastoma, and that it works through pathways that differ from available radiosensitizers, including temozolomide."

"Dr. Dinakaran’s exciting mechanistic work and the magnitude of the radiosensitization effect he identified suggests that zelenirstat, which has a broad spectrum of preclinical anticancer activity, might also be added to radiation for a variety of non-brain cancers, including cancers of the head and neck, lung, rectum, and uterine cervix." said John Mackey, CMO of Pacylex. "This opens up many new opportunities to benefit patients with common solid cancers."

On October 3, 2023 Iambic Therapeutics (formerly known as Entos), a biotechnology company developing novel therapeutics from its unique generative AI discovery platform, reported the closing of an oversubscribed $100 million Series B financing co-led by Ascenta Capital and Abingworth, and also including new investors NVIDIA, Illumina Ventures, Gradiant Corporation, Shanda, and independent board member Bill Rastetter (Press release, Iambic Therapeutics, OCT 3, 2023, View Source [SID1234637229]). Existing investors also participated, including Nexus Ventures, Catalio Capital Management, Coatue, FreeFlow, OrbiMed, Sequoia Capital, and Tao Capital. As part of the Series B, Iambic is delighted to welcome two new board members, Evan Rachlin, M.D., from Ascenta Capital and Kurt von Emster from Abingworth.

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"At Iambic, our world-class team has combined physics and AI to create a differentiated drug discovery platform that achieves a step-change in the speed and success rate for delivering best-in-class and first-in-class development candidates to clinic. With the Series B funding, we intend to advance multiple AI-discovered candidates into the clinic and expand our pipeline, demonstrating how the Iambic platform can deliver better therapeutics to patients in less time, with optimized target product profiles for greater likelihood of clinical success."
– Tom Miller, Ph.D., Co-founder and CEO of Iambic

"We were struck by the originality of these molecules, offering distinctive approaches in both deeply validated and more novel biological pathways," added Evan Rachlin, M.D., Co-founder and Managing Partner of Ascenta Capital. "Iambic’s platform enables a more creative and expansive exploration of how to treat diseases with profound unmet needs. We are delighted to partner with Tom and his extraordinary team in translating these thoroughly tested medicines into humans."

"Abingworth is proud to support the remarkably talented team at Iambic in its drive to revolutionize drug discovery and speed to the market with highly selective drugs" said Kurt von Emster, Managing Partner and Head of Life Sciences at Abingworth.

"AI-driven technologies, including methods that Iambic and NVIDIA researchers have built together, are charting a new path for researchers in the discovery of new therapeutic candidates," said Rory Kelleher, Director of Healthcare and Life Sciences at NVIDIA. "NVIDIA-accelerated computing and software are helping industry pioneers like Iambic drive scientific breakthroughs and our continued collaboration aims to speed innovation in drug discovery."

"We believe technology innovations powered by advanced computing and omics-derived data insights will transform drug discovery and pave the way for the next wave of groundbreaking medicines," said Ron Mazumder, Ph.D., MBA, Partner of Illumina Ventures. "Iambic’s physics-informed machine learning approach has yielded promising lead candidates with superior profiles in record time."

Since its 2021 Series A financing, Iambic has rapidly built its AI-driven discovery platform, which unifies state-of-the-art, physics-informed machine learning and experimental automation, and has demonstrated the platform’s success in identifying therapeutic candidates with differentiated drug profiles. In addition to building out a deep bench of AI and drug-discovery experts, Iambic has discovered two candidates to advance into the clinic: IAM-H1, a highly selective and brain-penetrant inhibitor of HER2 and its oncogenic mutants, and IAM-C1, a potential first-in-class selective dual CDK2/4 inhibitor to address unmet needs in terms of therapeutic window and treatment resistance in cell-cycle-driven cancers. Further, Iambic has extended its leadership position in the AI community, creating methods such as NeuralPLexer and OrbNet to drive its discovery platform.

With the funds raised in the Series B, Iambic intends to advance multiple candidates into clinical development, expand its pipeline with additional candidates with best-in-class and first-in-class potential, and continue to innovate and build next-generation AI and automation technologies for drug discovery. It plans to leverage NVIDIA technology such as the NVIDIA DGX Cloud AI supercomputing platform and the NVIDIA BioNeMo cloud service to accelerate discovery.

The company retains the technology created under its prior name of Entos Inc., adopting the new name of Iambic Therapeutics to reflect its transition to a company with the additional capability of clinical development of candidates identified through its AI-driven discovery platform.

About the Iambic Therapeutics Physics-Informed AI-Driven Discovery Platform

The Iambic Therapeutics AI-driven platform was created to address the most challenging design problems in drug discovery, incorporating the most current AI technologies and purpose-built tools from Iambic. The integration of physics principles into the platform’s AI architectures improves data efficiency and allows molecular models to venture widely across the space of possible chemical structures. The platform’s algorithms enable identification of new chemical mechanisms for engaging difficult-to-address biological targets, discovery of defined product profiles that optimize therapeutic window, and exploration of the chemical space to discover candidates for development with highly differentiated properties. Through close integration of AI-generated molecular designs with automated experimental execution, Iambic completes design-make-test cycles on a weekly cadence.