Abstract 2730: Beyond antibodies and CAR-T: Topologically-engineered, super-dimeric antibody-like molecules with dual Fc domains for trispecific, bivalent targeting of CD19, CD20, and Fcgamma receptors

作者: Capon, Benjamin Z. ; Edman, Ursula ; Capon, Daniel J. ; Punnonen, Juha ; Troitskaya, Larisa ; Chapin, Steven J. ; Law, Brian ; Fomin, Marina ; Gefter, Malcolm L. ; Chan, Nelson L. ; Lewis, Gavin M. ; Frank, Brendon

AbstractBackground: Depletion of B cells has resulted in major therapeutic benefits in autoimmune diseases and hematological malignancies. Several FDA-approved B cell-depleting antibody-based therapies are available, including antibody-drug conjugates, T cell engagers, CAR-T cells, and antibody variants with enhanced effector functions through Fc engineering. However, a significant unmet need remains in both oncology and autoimmune disease. All currently approved B cell-depleting therapies target a single B cell antigen, increasing potential for incomplete depletion and emergence of escape mutants that give rise to relapse and treatment failure.Methods: Here we describe trispecific antibody-like molecules generated using GEM-DIMER technology. In addition to bivalent target binding of both CD19 and CD20, the GEM-DIMER candidates are designed to have two Fc domains to enable powerful effector functions via cooperative binding of Fcgamma receptors. The approach is based on incorporation of a super-dimerization domain into the hinge region of an immunoglobulin heavy chain, enabling the combination of all of the components of two IgG antibodies into a single molecule. Using this approach, we generated GEM-DIMER candidates from rituximab and FMC63, the parental anti-CD19 antibody for anti-CD19 scFv used in approved CAR-T cell therapies.Results: CD19/CD20-targeting GEM-DIMER molecules demonstrated binding to both CD19 and CD20 with affinities comparable to the individual parent antibodies. Importantly, CD19/CD20-targeting GEM-DIMER molecules demonstrated robust depletion of human B cells in overnight cultures of whole blood. Moreover, antibody-dependent cellular cytotoxicity (ADCC) was demonstrated in co-cultures of the human B cell lymphoma cell line Raji and human peripheral blood mononuclear cells (PBMC). As expected, due to the presence of dual Fc domains, CD19/CD20-targeting GEM-DIMER molecules exhibited enhanced binding to Fcgamma receptors, further explaining the robust effector functions observed.Conclusions: CD19/CD20-targeting GEM-DIMER molecules are promising candidates to provide efficient depletion of both CD19+ and CD20+ cells, providing potential for broad and deep depletion of B cells with reduced risk of emergence of antigen escape variants. These data support the advancement of CD19/CD20-targeting GEM-DIMER molecules in multiple indications where depletion of CD19+ and/or CD20+ B cells is needed. Preparations for clinical investigation are ongoing.Citation Format: Daniel J. Capon, Nelson L. Chan, Larisa Troitskaya, Marina Fomin, Ursula Edman, Brendon Frank, Benjamin Z. Capon, Brian Law, Steven J. Chapin, Gavin M. Lewis, Malcolm L. Gefter, Juha Punnonen. Beyond antibodies and CAR-T: Topologically-engineered, super-dimeric antibody-like molecules with dual Fc domains for trispecific, bivalent targeting of CD19, CD20, and Fcgamma receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2730.

2023-12-31·Journal of Immunotoxicology

Current approaches to evaluate the function of cytotoxic T-cells in non-human primates

Review

作者: Collinge, Mark ; Kamperschroer, Cris ; Newsome, Courtni ; Piche, Marie-Soleil ; Rubio, Daniel ; Mitchell-Ryan, Shermaine ; Weinstock, Daniel ; Freebern, Wendy ; Molinier, Brigitte ; Frank, Brendon ; Lebrec, Hervé ; Genell, Caroline

Cytotoxic T-lymphocytes (CTL) are a subset of T-cells that play a critical role in protecting against intracellular infections and cancer, and have the ability to identify and kill infected or transformed cells expressing non-self peptides associated with major histocompatibility (MHC) Class I molecules. Conversely, aberrant CTL activity can contribute to immune-related pathology under conditions of overwhelming infection or autoimmunity. Disease-modifying therapeutics can have unintended effects on CTL, and a growing number of therapeutics are intended to either suppress or enhance CTL or their functions. The susceptibility of CTL to unintended effects from common therapeutic modalities underscores the need for a better understanding of the impact that such therapies have on CTL function and the associated safety implications. While there are reliable ways of quantifying CTL, notably via flow cytometric analysis of specific CTL markers, it has been a greater challenge to implement fit-for-purpose methods measuring CTL function in the context of safety studies of therapeutics. This review focuses on methods for measuring CTL responses in the context of drug safety and pharmacology testing, with the goals of informing the reader about current approaches, evaluating their pros and cons, and providing perspectives on the utility of these approaches for safety evaluation.

bioRxiv

Topologically engineered antibodies and Fc-fusion proteins: a new class of multifunctional therapeutic candidates for SARS-CoV-2, cancer, and other disease

作者: Ferguson, Ginger A. ; Martinelli, Rachel ; Jin, Jing ; Edman, Ursula ; Capon, Daniel J. ; Troitskaya, Larisa ; Simmons, Graham ; Fomin, Marina ; Gefter, Malcolm L. ; Capon, Benjamin Z. ; Frank, Brendon ; Chan, Nelson Lap Shun

The ability of antibodies and Fc-fusion proteins to bind multiple targets cooperatively is limited by their topol.Here we describe our discovery that ACE2 Fc-fusion proteins spontaneously cross-dimerize, forming topol. distinct "superdimers" that demonstrate extraordinary SARS-CoV-2 intra-spike cooperative binding and potently neutralize Omicron B.1.1.529 at least 100-fold better than eight clin. authorized antibodies.We also exploited crossdimerization to topol. engineer novel superdimeric antibodies and Fc-fusion proteins with antibody-like plasma half-lives to address cancer and infectious disease therapy.These include bispecific ACE2-antibody superdimers that potently neutralize all major SARS-CoV-2 variants, and bispecific anti-cancer and anti-viral antibody superdimers that are more potent than two-antibody cocktails.Superdimers are efficiently produced from single cells, providing a new therapeutic approach to many disease indications.

项与 Hinge Bio, Inc. 相关的新闻（医药）

2024-08-14

·GlobeNewswire-Health Care

Hinge Bio, Inc. Chief Scientific Officer, Daniel Capon, Ph.D., to Present its GEM-DIMER™ Platform Technology at the University of Oxford, Kennedy Institute of Rheumatology’s Annual Translational Research Conference

Dr. Capon will present Hinge Bio’s innovative GEM-DIMER™ platform as an invited speaker at the “Pioneering Technology” Session at Trinity College, Oxford at its Annual ConferenceBURLINGAME, Calif., Aug. 14, 2024 (GLOBE NEWSWIRE) -- Hinge Bio, Inc., a privately held biotechnology company in the San Francisco Bay Area, today announced that Daniel Capon, Ph.D., Founder & Chief Scientific Officer, will present the company’s GEM-DIMER technology at the Kennedy Institute’s Annual Conference, “From the Laboratory to the Clinic: 25 Years of Biological Therapy”, at Trinity College, University of Oxford, England. The Kennedy Institute of Rheumatology’s conference brings together a global audience of laboratory scientists, pharmaceutical and biotech executives, and clinicians to facilitate scientific exchange and collaboration leading to scientific progress in the translational research space. “I’m honored to present Hinge Bio’s revolutionary GEM-DIMER platform technology at the Kennedy Institute of Rheumatology’s annual conference, which this year celebrates the 25th anniversary of the approval of monoclonal antibodies and Ig fusion proteins and their entrance into routine use for rheumatoid arthritis, Crohn's disease and HER-2 positive breast cancer,” said Dr. Capon. Dr. Capon continued, “Antibodies and Fc fusion proteins have transformed medicine due to their ability to simultaneously engage disease targets and immune effector cells, leading to positive clinical outcomes in many disease types. GEM-DIMER technology creates novel antibody and Fc fusion protein topologies with more effective engagement of targets and immune cells via a process called cooperative binding. This process combines the most desirable properties of multiple clinically relevant antibodies into a single molecule, while retaining the robust stability and manufacturability of antibodies. Hinge Bio’s lead candidate, HB2198, which potently binds CD19, CD20 and Fc receptors, is designed to provide deep depletion of B cells to treat autoimmune diseases such as lupus/SLE and rheumatoid arthritis.” Presentation details are as follows: Title: Beyond Antibodies, Fc Fusion Proteins, and CAR-T: Topologically Engineered, Super-Dimeric Antibodies and Antigen Receptors Session: Pioneering Technology, Session 4 Session Date/Time: Thursday, August 29, 2024, at 9:30am GMT Presenter: Daniel Capon, Ph.D. ABOUT HINGE BIO Hinge Bio, Inc. is a privately held development-stage biotechnology company leveraging its proprietary GEM-DIMER™ platform to design and develop therapeutics leading to better treatment outcomes for patients living with autoimmune, inflammatory, and infectious disease, as well as cancer. The GEM-DIMER technology platform enables the creation of multivalent, multispecific antibody-based therapeutics that bind their targets cooperatively allowing for dramatically enhanced biological activity and unique functionality. GEM-DIMER technology was invented by Hinge Bio’s Chief Scientific Officer, Daniel Capon, Ph.D., the co-inventor of recombinant Factor VIII for hemophilia, and three foundational technologies that have transformed biological therapy: Fc fusion proteins (Genentech, Inc.), scFv-Zeta Chimeric Antigen Receptors for T cell therapy (Cell Genesys, Inc.), and genetically-modified mice producing repertoires of fully human antibodies capable of recognizing human disease targets (Abgenix, Inc.). Hinge Bio is advancing a pipeline of programs with an initial focus on autoimmune disease. Learn more at www.hingebio.com. CONTACTS Hinge Bio: Carin Rollins Chief Operating Officer carin.rollins@hingebio.com or info@hingebio.com

2024-04-08

·PRNewswire

Hinge Bio Presents Preclinical Data from its GEM-DIMER Program Targeting B Cell Depletion at the American Association for Cancer Research (AACR) Annual Meeting 2024

Hinge Bio's CD19, CD20, and Fc gamma receptor-targeting GEM-DIMER molecules are promising candidates to provide broad and deep depletion of B Cells with a reduced risk of antigen escape variants. BURLINGAME, Calif., April 8, 2024 /PRNewswire/ -- Hinge Bio, Inc., a privately-held biotechnology company, today announced that Daniel Capon, Ph.D., Chief Scientific Officer, and Juha Punnonen, M.D., Ph.D., Chief Development Officer, are presenting data from the company's GEM-DIMER program targeting B cell depletion at this year's American Association for Cancer Research (AACR) Annual Meeting 2024 in San Diego. "Hinge Bio is addressing areas of significant unmet medical need with its revolutionary GEM-DIMER platform, which uses topological engineering to combine the most desirable properties of multiple clinically relevant antibodies into a single molecule with dramatically improved activity, while retaining the robust stability and manufacturability of conventional antibodies," said Dr. Capon. Dr. Punnonen added, "This encouraging preclinical data supports advancing its GEM-DIMER candidate targeting CD19, CD20, and Fc gamma receptors as quickly as possible to clinical investigation in order to treat the large number of patients with B cell mediated diseases who remain resistant to currently approved treatments." Oral Poster details are as follows: Beyond antibodies and CAR-T: Topologically-engineered, super-dimeric antibody-like molecules with dual Fc domains for trispecific, bivalent targeting of CD19, CD20, and Fc gamma receptors Abstract #2730, Session PO.IM01.06 – Single Target and Bispecific Antibodies Session Date/Time: April 8, 2024, 1:30 PM – 5:00 PM, Section 6 Presenting Authors: Daniel Capon, PhD, Chief Scientific Officer; Juha Punnonen, MD, PhD, Chief Development Officer Summary: Hinge Bio's CD19/CD20-targeting GEM-DIMER molecules are promising candidates to provide efficient depletion of both CD19+ and CD20+ cells, providing potential for broad and deep depletion of B cells with reduced risk of emergence of antigen escape variants. These data support the advancement of these CD19/CD20-targeting GEM-DIMER molecules in multiple indications where depletion of CD19+ and/or CD20+ B cells is needed. Preparations for clinical investigation are ongoing. ABOUT HINGE BIO Hinge Bio is a privately held biotechnology company leveraging its powerful GEM-DIMER™ platform to develop therapeutics that address the problems of inadequate efficacy and resistance in diseases including cancer, inflammatory disease, and infectious disease. The GEM-DIMER platform creates multivalent, multispecific antibody-based therapeutics that bind their targets in a novel manner allowing for dramatically enhanced biological activity and unique functionality. The GEM-DIMER technology was invented by Hinge Bio's Chief Scientific Officer, Daniel Capon, Ph.D., the co-inventor of recombinant Factor VIII for hemophilia and three revolutionary technologies that have transformed biological therapy: Fc fusion proteins (Genentech, Inc.), scFv-Zeta Chimeric Antigen Receptors for T cell therapy (Cell Genesys, Inc.), and germline-modified mice producing repertoires of fully human antibodies capable of recognizing human disease targets (Abgenix, Inc.). Hinge Bio is advancing a pipeline of programs to treat autoimmune diseases, cancer, and infectious disease. Learn more at . CONTACTS Hinge Bio: Carin Rollins Chief Operating Officer [email protected] or [email protected] SOURCE Hinge Bio, Inc.

AACR会议

2023-09-06

·BioSpace

Allay Therapeutics Appoints Nicole Vitullo to Board of Directors

SAN JOSE, Calif.--(BUSINESS WIRE)-- Allay Therapeutics, a clinical-stage biotechnology company pioneering ultra-sustained analgesic products to transform post-surgical pain management and recuperation, today announced the appointment of Nicole Vitullo, venture partner at Arboretum Ventures, to its board of directors. “We’re thrilled to have Nicole join the Allay board and appreciate the continued support of Arboretum Ventures as we work to change the pain management paradigm and dramatically improve the post-surgical recovery experience for patients,” said Adam Gridley, Chief Executive Officer of Allay Therapeutics. “Nicole’s counsel, drawing from her long experience working with advanced-stage and commercial-stage biopharma companies, will be invaluable as we continue clinical development of our lead candidate ATX101 and advance additional Allay products into clinical studies worldwide.” Nicole is a longtime biotech investor and company advisor with extensive experience in both public and private investing, as a Partner with Domain Associates, a venture capital firm focused in the life sciences sector. She joined Arboretum as a venture partner in 2023. Nicole currently serves on the board of Esperion Therapeutics and Hinge Bio Inc. Her past board memberships include numerous companies that have entered transactions, including Achillion Pharmaceuticals (Alexion), Calixa Therapeutics (Cubist Pharmaceuticals), Celator Pharmaceuticals (Jazz Pharmaceuticals), Cerexa (Forest Laboratories), Durata Therapeutics (Actavis), Marinus Pharmaceuticals, Onyx Pharmaceuticals, and VentiRx Pharmaceuticals (Celgene). Nicole holds a bachelor’s degree in mathematics and MBA from the University of Rochester. “I’m excited to be part of Allay’s mission to develop medicines that help patients through extended painful recoveries and reduce their reliance on opioids following surgery. There is a huge unmet need for therapies that not only provide pain relief but also offer peace of mind for patients and their caregivers,” said Ms. Vitullo. “I look forward to working with Adam and the team as they work to bring these innovations to patients, providers and payors.” About Allay Therapeutics Allay Therapeutics is pioneering a new category of ultra-sustained pain therapeutics to transform post-surgical pain management and recuperation for patients and physicians. Allay’s proprietary technology platform combines validated non-opioid analgesics and biopolymers to create dissolvable therapeutics to deliver pain relief within a targeted site over weeks—an order of magnitude greater than the longest-lasting pain treatments currently available. The company’s lead investigational product candidate, ATX101, is currently being evaluated in a Phase 2 clinical study in total knee arthroplasties (TKA, also called total knee replacements). Allay unites a dynamic, global team of entrepreneurs, scientists, clinicians and innovators in the San Francisco Bay Area and Singapore. Learn more at allaytx.com. View source version on businesswire.com: Contacts Investors Adam Gridley adam.gridley@allaytx.com Media Chris Railey chris@tenbridgecommunications.com M: +1 617-834-093 Source: Allay Therapeutics View this news release online at:

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