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Monday Poster Session

Category: IBD

P2581 - Guselkumab Binding to CD64+ IL-23–Producing Myeloid Cells Enhances Potency for Neutralizing IL-23 Signaling

Monday, October 28, 2024
10:30 AM – 4:00 PM ET
Location: Exhibit Hall E
Jessica R. Allegretti, MD, MPH, FACG1, Raja Atreya, MD2, Maria T. Abreu, MD3, Amy Hart, PhD4, He (Hurley) Li, PhD4, Tom C. Freeman, PhD4, Eilyn Lacy, PhD4, Matthew DuPrie, PhD4, Phuc Bao, PhD5, Tina Smets, BS6, Joshua Wertheimer, PhD4, Indra Sarabia, PhD5, Kristen Kohler, PhD5, Anne Fourie, PhD5, Kacey Sachen, PhD5
1Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 2Erlangen University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Baden-Wurttemberg, Germany; 3Crohn's and Colitis Center, University of Miami Miller School of Medicine, Miami, FL; 4Janssen Research & Development, LLC, a Johnson & Johnson Company, Spring House, PA; 5Janssen Research & Development, LLC, a Johnson & Johnson Company, San Diego, CA; 6Janssen Research & Development, LLC, a Johnson & Johnson Company, Beerse, Antwerpen, Belgium

Introduction: IL-23 is implicated in the pathogenesis of inflammatory bowel disease (IBD) and myeloid cells that express FcγRI (CD64) have been identified as a primary source of IL-23 in inflamed IBD gut tissue. Guselkumab (GUS), risankizumab (RZB), and mirikizumab (MIRI) are monoclonal antibodies that bind the IL-23p19 subunit. GUS has a native Fc domain; RZB and MIRI contain mutations in the Fc domain that reduce binding to FcgRs.

Methods: We evaluated CD64 and IL-23 transcript expression in IBD patient gut biopsies, binding of GUS, RZB, and MIRI to IL-23 and CD64, and their potency for neutralization of recombinant or endogenous, locally produced, IL-23 in in vitro assays. IL23A, IL12B, and FCGR1A (CD64) expression was analyzed from bulk and single-cell RNA sequencing datasets. IL-23 binding affinity was evaluated using a kinetic exclusion assay. Binding of GUS, RZB, and MIRI to CD64 was assessed in cells with recombinant expression of CD64. Potency for inhibition of recombinant IL-23 was evaluated in human peripheral blood mononuclear cells (PBMCs). Potency for inhibition of endogenous, locally produced IL-23 was determined in a co-culture of THP-1 (a CD64+ IL-23-producing monocyte cell line) and an IL-23 reporter cell line (measuring biologically active IL-23).

Results: Analysis of RNA sequencing datasets showed FCGR1A, IL23A, and IL12B were significantly increased in inflamed versus non-inflamed IBD gut biopsies, and IL23A was predominantly expressed by FCGR1A-expressing myeloid cells. GUS, RZB, and MIRI displayed single-digit picomolar binding affinity for IL-23. GUS demonstrated binding to CD64, while no binding was observed for RZB or MIRI. GUS, RZB, and MIRI demonstrated comparable potency for inhibition of signaling by recombinant IL-23 in human PBMCs. However, in the co-culture assay, GUS demonstrated enhanced potency compared to RZB and MIRI for inhibition of IL-23 signaling.

Discussion: Our transcriptomic analysis confirmed CD64+ myeloid cells are a key source of IL-23 production in inflamed IBD gut tissue. GUS binding to CD64 on IL-23–producing cells likely contributed to the enhanced potency of GUS compared to RZB and MIRI for inhibition of IL-23 in the co-culture assay. These in vitro data support a hypothesis for optimal localization of GUS in inflamed tissues where CD64+ IL-23–producing myeloid cells are increased and in proximity to IL-23–responsive lymphoid cells, enabling GUS to more potently neutralize IL-23 at its source of production.


Disclosures:
Jessica R. Allegretti: Abbvie – Consultant, Speakers Bureau. Artugen – Consultant. Bristol Myers Squibb – Consultant, Speakers Bureau. Ferring – Consultant. Finch Therapeutics – Consultant. Janssen – Consultant. Merck – Grant/Research Support. Pfizer – Consultant. Seres – Consultant.
Raja Atreya: AbbVie – Consultant, Honoraria. Abivax – Consultant, Speakers fees. Amgen – Consultant, Honoraria. Arena Pharmaceuticals – Consultant, Honoraria. AstraZeneca – Consultant, Speakers fees. Biogen – Consultant, Honoraria. Boehringer Ingelheim – Consultant, Honoraria. Bristol Myers Squibb – Consultant, Honoraria. Celgene – Consultant, Honoraria. Celltrion Healthcare – Consultant, Honoraria. Dr. Falk Pharma – Consultant, Honoraria. Ferring – Consultant, Honoraria. Fresenius Kabi – Consultant, Honoraria. Galapagos – Consultant, Honoraria. Gilead – Consultant, Honoraria. GSK – Consultant, Honoraria. InDex Pharmaceuticals – Consultant, Honoraria. Janssen – Consultant, Honoraria. Kiniksa Pharmaceuticals – Consultant, Honoraria. Merk Sharp & Dohme – Consultant, Honoraria. Novartis – Consultant, Honoraria. Pfizer – Consultant, Honoraria. Roche – Consultant, Honoraria. Samsung Bioepis – Consultant, Honoraria. Stelic – Consultant, Honoraria. Sterna Biologicals – Consultant, Honoraria. Takeda – Consultant, Honoraria. Tillotts – Consultant, Honoraria.
Maria Abreu: AbbVie – Advisory Committee/Board Member, Consultant. Alimentiv – Lecturing Fee. Arena Pharmaceuticals Inc. – Advisory Committee/Board Member, Consultant. Bristol Myers Squibb – Advisory Committee/Board Member, Consultant. Celsius Therapeutics – Advisory Committee/Board Member, Consultant. Gilead – Advisory Committee/Board Member, Consultant. Janssen – Advisory Committee/Board Member, Consultant, Lecturing Fee. Lilly – Advisory Committee/Board Member, Consultant. Pfizer – Advisory Committee/Board Member, Consultant. Prime – Lecturing Fee. Prometheus Biosciences – Advisory Committee/Board Member, Consultant. UCB – Advisory Committee/Board Member, Consultant. WedMD Global LLC – Lecturing Fee.
Amy Hart: Janssen – Employee, Stock Options.
He (Hurley) Li: Janssen – Employee, Stock Options.
Tom C. Freeman: Janssen – Employee, Stock Options.
Eilyn Lacy: Janssen – Employee, Stock Options.
Matthew DuPrie: Janssen – Employee, Stock Options.
Phuc Bao: Janssen – Employee, Stock Options.
Tina Smets: Janssen – Employee, Stock Options.
Joshua Wertheimer: Janssen – Employee, Stock Options.
Indra Sarabia: Janssen – Employee, Stock Options.
Kristen Kohler: Janssen – Employee, Stock Options.
Anne Fourie: Janssen – Employee, Stock Options.
Kacey Sachen: Janssen – Employee, Stock Options.


Jessica R. Allegretti, MD, MPH, FACG1, Raja Atreya, MD2, Maria T. Abreu, MD3, Amy Hart, PhD4, He (Hurley) Li, PhD4, Tom C. Freeman, PhD4, Eilyn Lacy, PhD4, Matthew DuPrie, PhD4, Phuc Bao, PhD5, Tina Smets, BS6, Joshua Wertheimer, PhD4, Indra Sarabia, PhD5, Kristen Kohler, PhD5, Anne Fourie, PhD5, Kacey Sachen, PhD5. P2581 - Guselkumab Binding to CD64+ IL-23–Producing Myeloid Cells Enhances Potency for Neutralizing IL-23 Signaling, ACG 2024 Annual Scientific Meeting Abstracts. Philadelphia, PA: American College of Gastroenterology.