2232: Guselkumab, an IL-23p19 Subunit–specific Monoclonal Antibody, Is Able to Bind CD64⁺ Myeloid Cells, Potently Neutralize IL-23 Produced from the Cells, and Mediate Internalization of IL-23

Dennis McGonagle¹, raja atreya², Maria Abreu³, James Krueger⁴, Kilian Eyerich⁵, Robert Bissonnette⁶, Kacey Sachen⁷, Carrie Greving⁷, Brian Stoveken⁸, Deepa Hammaker⁷, Kristin Leppard⁸, John Hartman⁸, Phuc Bao⁷, Eilyn Lacy⁸, Indra Sarabia⁷, Janise Deming⁷, Matthew Duprie⁸, Joseph Brown⁷, Christopher T Ritchlin⁹, Iain McInnes¹⁰, Matthieu Allez¹¹ and Anne Fourie⁷, ¹Leeds Biomedical Research Centre, University of Leeds, Leeds, United Kingdom, ²Erlangen University Hospital, Friedrich-Alexander-Univrsität Erlangen-Nürnberg, Erlangen, Germany, ³University of Miami, Leonard Miller School of Medicine, Miami, FL, ⁴The Rockefeller University, Laboratory for Investigative Dermatology, New York, NY, ⁵Medical Center, University of Freiburg; Karolinska Institute, Department of Medicine - Division of Dermatology and Venereology, Stockholm, Sweden, ⁶Innovaderm Research Inc, Medical Director, Montréal, QC, Canada, ⁷Janssen Research and Development, LLC, Immunology, San Diego, CA, ⁸Janssen Research & Development, LLC, Therapeutics Discovery, Spring House, PA, ⁹University of Rochester Medical School, Allergy, Immunology & Rheumatology Division, Canandaigua, NY, ¹⁰University of Glasgow, Glasgow, United Kingdom, ¹¹Hôpital Saint-Louis, Université Paris Cité, Paris, France

Background/Purpose: Monoclonal antibodies (mAbs) targeting the interleukin (IL)-23p19 subunit are effective in treating psoriatic disease; however, their molecular attributes may translate to differences in clinical efficacy. Guselkumab (GUS) is a fully human anti-IL-23p19 subunit IgG1 mAb with a native Fc region, whereas risankizumab (RZB) is a humanized anti-IL-23p19 subunit IgG1 mAb with a mutated Fc region. Binding of mAbs to Fcγ receptors (FcγRs) is of particular interest, because FcγRI (CD64)⁺ IL-23–producing myeloid cells are increased within inflamed tissue of patients with psoriatic disease. Furthermore, in psoriatic arthritis, joint disease activity is positively correlated with the frequency of peripheral CD64⁺ monocytes. Here, in vitro functional characteristics of the antigen-binding and Fc regions of GUS and RZB, as well as implications of CD64 binding for mAb function and IL-23 neutralization, were explored.

Methods: IL-23 binding affinity of GUS and RZB was evaluated using a kinetic exclusion assay. Cellular potency was measured by mAb impact on IL-23–induced STAT3 phosphorylation in human peripheral blood mononuclear cells. Binding of GUS and RZB to FcγRs was assessed in cells transfected with individual FcγRs. Primary human monocytes differentiated into an inflammatory state were utilized in flow cytometry assays to assess GUS and RZB binding to CD64 and capture of locally produced endogenous IL-23. Cellular activation following mAb binding to CD64 on inflammatory monocytes was assessed using a 41-plex cytokine bead assay. Internalization of IL-23, GUS, and RZB within CD64⁺ macrophages was assessed using live cell confocal imaging.

Results: GUS and RZB displayed comparable picomolar binding affinity for IL-23 and similar high potency for inhibiting IL-23–induced STAT3 phosphorylation. GUS showed the strongest binding to CD64 versus other FcγRs; RZB had negligible binding to any FcγR. GUS, but not RZB, showed dose-dependent Fc-mediated binding to CD64 on inflammatory monocytes, and CD64-bound GUS was able to capture endogenous IL-23 secreted from the same cells. GUS binding to CD64 on inflammatory monocytes did not induce or enhance cytokine production. GUS, but not RZB, bound to the cell surface of CD64⁺ macrophages and mediated internalization of IL-23 to low pH intracellular compartments.

Conclusion: Compared with RZB, GUS has unique attributes that allow it to simultaneously bind CD64⁺ myeloid cells via its native Fc region and neutralize IL-23 with high affinity and potency. These data suggest a potential mechanistic benefit through enrichment of GUS within inflamed tissue of patients with psoriatic disease, where CD64⁺ IL-23–producing myeloid cells are increased, enabling potent neutralization of IL-23 at its source and removal of IL-23 from inflamed tissue via internalization.


D. McGonagle: AbbVie, 2, 5, 6, Celgene, 2, 5, 6, Janssen, 2, 5, 6, Merck, 2, 5, 6, Novartis, 2, 5, 6, Pfizer, 2, 5, 6, UCB, 2, 5, 6; r. atreya: AbbVie, 2, 6, Amgen, 2, 6, Arena Pharmaceuticals, 2, 6, Biogen, 2, 6, Boehringer Ingelheim, 2, 6, Bristol Myers Squibb, 2, 6, Celgene, 2, 6, Celltrion Healthcare, 2, 6, Dr. Falk Pharma, 2, 6, Ferring, 2, 6, Fresenius Kabi, 2, 6, Galapagos, 2, 6, Gilead, 2, 6, GlaxoSmithKline, 2, 6, InDex Pharmaceuticals, 2, 6, Janssen, 2, 6, Kliniksa Pharmaceuticals, 2, 6, Merk Sharp & Dohme, 2, 6, Novartis, 2, 6, Pfizer, 2, 6, Roche, 2, 6, Samsung Bioepsis, 2, 6, Stelic, 2, 6, Sterna Biologicals, 2, 6, Takeda, 2, 6, Tillotts, 2, 6; M. Abreu: AbbVie, 2, 6, Alimentiv, 2, 6, Amgen, 2, 6, Arena Pharmaceuticals, 2, 6, Bristol Myers Squibb, 2, 6, Celsius Therapeutics, 2, 6, Eli Lilly and Company, 2, 6, Gilead Sciences, 2, 6, Janssen Pharmaceuticals, 2, 6, Microba Life Sciences, 2, 6, Pfizer Pharmaceutical, 2, 6, Prometheus Biosciences, 2, 6, Takeda Pharmaceuticals, 2, 6, UCB Biopharma SRL, 2, 6, WebMD Global LLC, 2, 6; J. Krueger: AbbVie, 2, 5, 6, Aclaris, 2, 6, Akros, 5, Allergan, 2, 5, 6, Almirall, 2, 6, Amgen, 2, 5, 6, Arena, 2, 6, Aristea, 2, 6, Asana, 2, 6, Aurigene, 2, 6, Avillion, 5, Biogen, 2, 5, 6, Boehringer Ingelheim, 2, 5, 6, Bristol Myers Squibb, 2, 5, 6, Eli Lilly, 2, 5, 6, Escalier, 2, 6, Exicure, 5, Galapagos, 2, 6, Incyte, 5, Innovaderm, 5, Janssen, 2, 5, 6, Kyowa Kirin, 5, MoonLake Immunotherapeutics, 2, 6, Nimbus Lackshmi, 2, 5, 6, Novan, 5, Novartis, 2, 5, 6, Parexel, 5, Pfizer, 2, 5, 6, Regeneron, 5, Sanofi, 2, 6, Sienna Biopharmaceuticals, 2, 6, Sun Pharma, 2, 6, Target-Derm, 2, 6, UCB, 2, 5, 6, Valeant, 2, 6, Ventyx, 2, 6, Vitae Pharmaceuticals, 5; K. Eyerich: AbbVie, 1, 6, Almirall, 1, 6, Boehringer Ingelheim, 1, 6, Bristol Myers Squibb, 1, 6, Eli Lilly, 1, 6, Hexal, 1, 6, Janssen, 1, 6, LEO Pharma, 1, 6, Novartis, 1, 6, Pfizer, 1, 6, Sanofi, 1, 6, UCB, 1, 6; R. Bissonnette: AbbVie, 1, 2, 5, 6, Almirall, 1, 2, 5, 6, Alumis, 1, 2, 5, 6, Amgen, 1, 2, 5, 6, AnaptysBio, 1, 2, 5, 6, Arcutis, 1, 2, 5, 6, Aristea, 1, 2, 5, 6, Bausch Health, 1, 2, 5, 6, Boehringer Ingelheim, 1, 2, 5, 6, Boston, 1, 2, 5, 6, Bristol Myers Squibb, 1, 2, 5, 6, Dermavant, 1, 2, 5, 6, Eli Lilly, 1, 2, 5, 6, Escalier, 1, 2, 5, 6, Innovaderm Research, 3, 11, Janssen, 1, 2, 5, 6, Kyowa Kirin, 1, 2, 5, 6, LEO Pharma, 1, 2, 5, 6, Nimbus, 1, 2, 5, 6, Novartis, 1, 2, 5, 6, Pfizer, 1, 2, 5, 6, Regeneron, 1, 2, 5, 6, Sienna, 1, 2, 5, 6, UCB, 1, 2, 5, 6, Ventyx Biosciences, 1, 2, 5, 6, Xencor, 1, 2, 5, 6; K. Sachen: Janssen, 3, Johnson & Johnson, 11; C. Greving: Janssen, 3, Johnson & Johnson, 11; B. Stoveken: Janssen, 3, Johnson & Johnson, 11; D. Hammaker: Janssen, 3, Johnson & Johnson, 11; K. Leppard: Janssen, 3, Johnson & Johnson, 11; J. Hartman: Janssen, 3, Johnson & Johnson, 11; P. Bao: Janssen, 3, Johnson & Johnson, 11; E. Lacy: Janssen, 3, Johnson & Johnson, 11; I. Sarabia: Janssen, 3, Johnson & Johnson, 11; J. Deming: Janssen, 3, Johnson & Johnson, 11; M. Duprie: Janssen, 3, Johnson & Johnson, 11; J. Brown: Janssen, 3, Johnson & Johnson, 11; C. Ritchlin: AbbVie, 2, 5, 6, Amgen, 2, BMS, 2, Eli Lilly, 2, Gilead, 2, Janssen, 2, Novartis, 2, Pfizer, 2, 5, 6, UCB, 2, 6; I. McInnes: AbbVie, 2, Amgen, 2, AstraZeneca, 2, Bristol Myers Squibb, 2, 5, Cabaletta, 2, 11, Causeway Therapeutics, 2, 11, Celgene, 2, 5, Compugen, 2, 11, Dextera, 11, Eli Lilly, 2, EveloBio, 1, 2, 4, 11, Gilead, 2, Janssen, 2, 5, Moonlake, 2, NHS GGC, 4, Novartis, 2, 5, Pfizer, 2, Sanofi, 2, UCB, 2, 5, Versus Arthritis, 12, Trustee Status; M. Allez: AbbVie, 2, 6, Amgen, 2, 6, Biogen, 2, 6, Boehringer Ingelheim, 2, 6, Bristol Myers Squibb, 2, 6, Celgene, 2, 6, Celltrion, 2, 6, Eli Lilly, 2, 6, Ferring, 2, 6, Galapagos, 2, 6, Genentech/Roche, 2, 5, 6, Gilead, 2, 6, IQVIA, 2, 6, Janssen, 2, 5, 6, Novartis, 2, 6, Pfizer, 2, 6, Takeda, 2, 5, 6, Tillotts, 2, 6; A. Fourie: Janssen, 3, Johnson & Johnson, 11.