A new approach to drugging a difficult cancer target

Phys.org | March 15, 2019

One of the most common cancer-promoting genes, known as Myc, is also one of the most difficult to target with drugs. Scientists have long tried to develop drugs that block the Myc protein, but so far their efforts have not been successful. Now, using an alternative strategy, MIT researchers have discovered a compound that can reduce Myc activity by tying up the protein that is Myc's usual binding partner, leaving Myc partnerless and unable to perform its usual functions. The research team, led by Angela Koehler, an assistant professor of biological engineering and a member of MIT's Koch Institute for Integrative Cancer Research, found that the compound they developed could suppress tumor growth in mice with certain types of cancer. The compound has been licensed by an MIT spinout that is now seeking to develop more powerful versions that could potentially be tested in human patients.

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Mustang Bio Announces First Data from Ongoing Multicenter Phase 1/2 Clinical Trial Evaluating MB-106 CAR-T Cell Therapy

Globenewswire | August 17, 2023

Mustang Bio Inc. a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for difficult-to-treat cancers and rare genetic diseases, today announced the first data from the indolent lymphoma cohort of the Company’s ongoing multicenter Phase 1/2 clinical trial evaluating MB-106, a first-in-class CD20-targeted, autologous CAR-T cell therapy for the treatment of relapsed or refractory B-cell non-Hodgkin lymphomas (“B-NHL”) and chronic lymphocytic leukemia (“CLL”), demonstrating clinical responses as well as safety and efficacy consistent with the ongoing Phase 1/2 clinical trial taking place at Fred Hutchinson Cancer Center (“Fred Hutch”). Initial data were presented by Mazyar Shadman, M.D., M.P.H., Study Chair, Associate Professor and physician at Fred Hutch and University of Washington, at the 5th International Workshop on CAR-T and Immunotherapies (“iwCAR-T”). Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, “We are encouraged that the first data from the multicenter trial of our lead candidate, MB-106, show clinical responses and that the trial is on track to achieve results consistent with those from the ongoing trial taking place at Fred Hutch. Overall, MB-106 continues to exhibit high efficacy and a favorable safety profile compared to currently approved autologous CAR-Ts. We expect to provide an additional update on dose escalation and report response data at a major medical meeting later this year.” The multicenter study data show clinical responses in four of four patients with relapsed or refractory indolent NHL at the starting dose of 3.3 x 106 CAR-T cells/kg, a dose comparable to that employed for the majority of the indolent lymphoma patients in the Fred Hutch trial. The multicenter data also show persistence of CAR-T cells at 6+ months and favorable safety data with only Grade 1 cytokine release syndrome (“CRS”) reported to date. Two patients with follicular lymphoma had complete response (“CR”) by both PET-CT and bone marrow, one of whom had been previously treated with a CD19-directed CAR-T. A third patient, with a diagnosis of Waldenstrom macroglobulinemia (“WM”), who had nine prior treatments and high disease burden, achieved complete metabolic response by PET-CT, morphologic clearance of lymphoma in bone marrow, and resolution of the IgM monoclonal protein. The fourth patient, with a diagnosis of hairy cell leukemia variant, who had been heavily transfusion dependent, continues to have stable disease with decreased disease in his bone marrow and achieved complete transfusion independence, which is ongoing at 6+ months. “MB-106 continues to show potential as an immunotherapy option for patients with a wide range of hematologic malignancies, including patients previously treated with CD19-directed CAR-T cell therapy,” said Mazyar Shadman, M.D., M.P.H., who holds the Innovators Network Endowed Chair at Fred Hutch and is the Study Chair, as well as Associate Professor and physician at Fred Hutch and University of Washington. “We are excited that the first data from the expanded evaluation of MB-106 are similar in safety as what we’ve seen to date in the ongoing Phase 1/2 clinical trial at Fred Hutch. Additionally, the data from the ongoing clinical trial at Fred Hutch continue to demonstrate a high rate of complete and durable responses.” Dr. Shadman also presented data from the ongoing Fred Hutch Phase 1/2 clinical trial, specific to two B-NHL cohorts, follicular lymphoma (“FL”) and WM. In the FL data cohort (n=20), an overall response rate (“ORR”) of 95% was seen, of which 80% of patients experienced a CR, and 15% had a partial response. The CR patients include a patient who was previously treated with a CD19-directed CAR-T cell therapy. Of the six patients who experienced CRS, only one had Grade 2. Ten patients continue to experience CR for more than 10 months, four patients have experienced CR for more than two years (all ongoing), and the first patient enrolled has sustained CR for more than 3 years. In the WM cohort (n=6), all of whom had received prior Bruton tyrosine kinase inhibitor, two patients experienced CR, one of whom continues to be in CR at more than 22 months. No patients experienced CRS or immune effector cell-associated neurotoxicity syndrome over Grade 2. None of the six WM patients have needed to start new therapy for their disease. As previously reported, Mustang plans to treat patients with WM in the Phase 1 portion of its multicenter clinical trial to support a fast-to-market Phase 2 strategy for this indication and received Orphan Drug Designation from the U.S. Food and Drug Administration (“FDA”). There is currently no FDA-approved CAR-T cell therapy for WM, and the first patient in the pivotal Phase 2 WM trial is expected to be treated in mid-2024, which could enable top-line data as early as mid-2026. By the end of 2023, we anticipate confirming this strategy at an end-of-Phase 1 meeting with the US Food and Drug Administration (FDA). Furthermore, Mustang anticipates requesting regenerative medicine advanced therapy (RMAT) designation for WM from the FDA in 2024. Finally, data from the Fred Hutch clinical trial also support the potential of MB-106 to be administered as outpatient therapy and provide a best-in-class immunotherapy option for patients treated previously with CD19-directed CAR-T cell therapy. About Mustang’s Multicenter MB-106 Phase 1/2 Clinical Trial The five-center Phase 1/2 clinical trial is a three-arm study targeting CLL and B-NHL, including FL, diffuse large B-cell lymphoma and mantle cell lymphoma. We anticipate adding a sixth center by the end of 2023. The Mustang-sponsored multicenter clinical trial is using the same lentiviral vector as the Fred Hutch-sponsored single-center trial. Included in the eligibility criteria are patients who have relapsed after treatment with CD19 CAR-T cell therapy. Additionally, the FL arm will evaluate other indolent histologies including Waldenstrom macroglobulinemia, a rare type of B-NHL for which the U.S. Food and Drug Administration granted MB-106 Orphan Drug Designation. Patients will be enrolled in one of three arms, based on their primary diagnosis; escalating MB-106 dose levels will be tested independently in each arm using a 3+3 design. A total of up to 18 patients are anticipated to be treated in each Phase 1 arm, including six patients at the maximum tolerated dose in each independent arm. Safety of each dose level will be reviewed for each arm until the maximum tolerated dose has been reached and the recommended Phase 2 dose (“RP2D”) has been established for each arm. An assessment of the safety and tolerability of the dose will be made by the Safety Review Committee based on the data from the 28-day dose-limiting toxicity observation period. In Phase 2, specific arms of relapsed or refractory CD20-positive B-cell hematologic malignancies will be treated with MB-106 at the respective RP2D for each arm. The two top priorities are WM and diffuse large B-cell lymphoma (DLBCL) relapsed from prior CD19 CAR-T therapy. Each arm will initially include up to 20 patients. Based on the results of the interim analysis, up to an additional 51 patients may be added to each of the arms. About MB-106 (CD20-targeted autologous CAR-T Cell Therapy) CD20 is a membrane-embedded surface molecule which plays a role in the differentiation of B-cells into plasma cells. The CAR-T was developed by Mustang’s research collaborator, Fred Hutch, in the laboratories of the late Oliver Press, M.D., Ph.D., and Brian Till, M.D., Associate Professor in the Clinical Research Division at Fred Hutch, and was exclusively licensed to Mustang in 2017. The lentiviral vector drug substance used to transduce patients’ cells to create the MB-106 drug product produced at Fred Hutch has been optimized as a third-generation CAR derived from a fully human antibody. MB-106 is currently in a Phase 1/2 open-label, dose-escalation trial at Fred Hutch in patients with B-NHLs and CLL. The same lentiviral vector drug substance produced at Fred Hutch is used to transduce patients’ cells to create the MB-106 drug product produced at Mustang Bio’s Worcester, MA, cell processing facility for administration in the multicenter Phase 1/2 clinical trial under Mustang Bio’s IND. It should be noted that Mustang Bio has introduced minor improvements to its cell processing to facilitate eventual commercial launch of the product. In addition, prior to commercial launch, Mustang Bio will replace the Fred Hutch lentiviral vector drug substance with vector produced at a commercial manufacturer. Additional information on the trials can be found at http://www.clinicaltrials.gov using the identifier NCT05360238 for the multicenter trial and NCT03277729 for the ongoing trial at Fred Hutch. On May 18, 2023 Mustang Bio entered into an Asset Purchase Agreement, as amended by the First Amendment, dated as of June 29, 2023 and a Second Amendment, dated as of July 28, 2023 pursuant to which it agreed to sell its assets primarily pertaining to the manufacturing and production of cell and gene therapies located at its cell processing facility in Worcester, MA; and, subject to the satisfaction of certain conditions, its leasehold interest in that facility. Concurrent with the Second Amendment, Mustang closed the transaction under the terms of the amended asset purchase agreement and entered into manufacturing services agreements with the purchaser to provide for the continued production of the MB-106 drug product. For additional information, please refer to the Form 8-Ks filed by Mustang Bio with the U.S. Securities and Exchange Commission (“SEC”) on May 22, 2023, June 30, 2023 and July 31, 2023. About Mustang Bio Mustang Bio, Inc. is a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for difficult-to-treat cancers and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR-T therapies across multiple cancers, as well as lentiviral gene therapies for severe combined immunodeficiency. Mustang’s common stock is registered under the Securities Exchange Act of 1934, as amended, and Mustang files periodic reports with the U.S. Securities and Exchange Commission (“SEC”). Mustang was founded by Fortress Biotech, Inc.

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Medical

AbCellera Expands Multi-Target Antibody Discovery Collaboration with Regeneron

businesswire | September 21, 2023

AbCellera announced that it has expanded its existing multi-target collaboration with Regeneron to discover therapeutic antibodies for up to eight targets selected by Regeneron, increased from the original four. “Having successfully delivered on two challenging discovery campaigns under the original agreement, we are excited to expand the scope of our collaboration with Regeneron to include up to four additional targets,” said Carl Hansen, Ph.D., founder and CEO of AbCellera. “We look forward to using our antibody discovery and development engine to bolster Regeneron’s preclinical portfolio and help identify promising candidates for their programs.” The collaboration, which began in March 2020, leverages AbCellera’s antibody discovery engine and Regeneron’s VelocImmune® mice to identify novel therapeutic antibodies. AbCellera has initiated programs for all four of the original targets, with Regeneron exercising its rights to advance antibody candidates into further preclinical development for the two programs that have been completed. Under the terms of the agreement, Regeneron has the right to develop and commercialize therapeutic antibodies resulting from the collaboration. AbCellera receives research payments and is eligible to receive downstream clinical and regulatory milestone payments and royalties on net sales of products. About AbCellera Biologics Inc. AbCellera is breaking the barriers of conventional antibody drug discovery to bring better medicines to patients, sooner. AbCellera’s engine integrates expert teams, technology, and facilities with the data science and automation needed to propel antibody-based medicines from target to clinic in nearly every therapeutic area with precision and speed. AbCellera provides innovative biotechs and leading pharmaceutical companies with a competitive advantage that empowers them to move quickly, reduce cost, and tackle the toughest problems in drug development.

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Industry Outlook

Enveda Biosciences unveils new AI algorithm to unlock nature’s chemical code

Businesswire | June 26, 2023

Enveda Biosciences, a biotechnology company discovering new medicines from natural sources, released the details of one of its foundational AI models, MS2Mol, in a pre-print posted on ChemRxiv. MS2Mol is designed to predict the structure of metabolites, which are the building blocks and breakdown products of the cell. Despite their essential role in all cell processes, it is estimated that less than 1% of all naturally-occurring metabolites are known to science. The ability of MS2Mol to rapidly predict the structure of previously uncharacterized metabolites without lengthy laboratory experimentation enables their prioritization as potential drug candidates and expands our knowledge of the natural world. “Metabolites have a long and successful history as the basis for impactful drugs including aspirin, taxol, metformin, artemisinin, and statins. This is particularly impressive given that we, as scientists, have barely scratched the surface of natural metabolite diversity. With MS2Mol integrated into our platform, we can tap evolutionary chemical intelligence for the next generation of powerful medicines at scale,” said Viswa Colluru, Ph.D., founder and CEO of Enveda. Enveda’s proprietary platform solves the long-standing obstacles in natural product drug development including active molecule identification, property and structure prioritization, amenability to medicinal chemistry, and large-scale material access. The company recently closed its Series B1 round and will progress multiple platform-derived molecules to the clinic in 2023 and 2024 across inflammation, fibrosis, and neurosensory indications. “Metabolite identification used to be a process that was time-consuming, prone to failure, and required highly specialized expertise. MS2Mol takes the most easily accessible – but extremely cryptic – form of data on metabolites, the mass spectrum, and translates it into a language that scientists can use: the chemical structure. Solving this translation problem with AI puts the most useful information in the hands of drug hunters at massive scale,” said David Healey, Ph.D., VP of Data Science at Enveda and senior author of the pre-print. “While other companies use AI to predict what you want to buy, we use AI to discover what humanity needs to know,” said Tom Butler, Ph.D., VP of Machine Learning at Enveda and first author of pre-print. “Unlocking bioactive chemistry honed by billions of years of evolution for modern drug discovery has led us to discover a slate of exciting candidate medicines at a remarkable pace,” said Sotirios Karathanasis, Ph.D., CSO at Enveda. “We look forward to modification of disease pathophysiology by our medicines in the clinic and redefinition of the concept of target undruggability with the Enveda platform.” With the creation of MS2Mol, Enveda continues to deliver field-changing technology for the discovery and utilization of natural metabolites to drive novel therapeutic development. About Enveda Biosciences Enveda Biosciences is a biotechnology company building the first high-resolution chemical map of the natural world to tackle the toughest problems in drug discovery. Enveda’s platform is the world’s most advanced drug discovery search engine from the expanse of nature’s unknown chemistry, building on years of cutting-edge advancements at the intersection of metabolomics and machine learning. Complementing its breakthrough technology, Enveda’s team includes seasoned drug hunters with decades of experience in the pharmaceutical industry working with preeminent data scientists.

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