Abstract Background Inflammatory bowel disease (IBD) is a complex disease characterized by a dysregulated host immunity. CCR9 is the main activator of gut tropism in the lymphocytes and promotes their migration into the lamina propria, making it a rational therapeutic target. SBR5 is a candidate to best-in-class anti-CCR9 monoclonal antibody with enhanced Antibody-Dependent Cellular Cytotoxicity (ADCC). SRB5 effectively depletes CD4+CCR9+ T cells, avoiding ligand competition, in intestinal biopsies and blood of Crohn’s Disease (CD) and Ulcerative Colitis (UC) patients, leading to a marked reduction in pro-inflammatory cytokines and restoration of immune homeostasis. With this study, we aimed to evaluate the efficacy of SRB5 compared to the External Benchmark Antibody–CCR9 (EBACCR9). For this purpose, we based our comparison on an ex vivo model using intestinal biopsies from UC and CD patients. Methods A prospective study was conducted in a cohort of IBD patients from Hospital Universitario Santiago de Compostela and Hospital Álvaro Cunqueiro, Vigo. Intestinal biopsies were collected in colonoscopies with activity (Mayo Endoscopic Score 1 in UC and presence of ulcers in CD). Direct comparative studies were performed between SRB5 and EBA-CCR9 in these biopsies. Depletion of CD4+ CCR9+ Tcells isolated from lamina propria was quantified by flow cytometry. Results Head-to-head analyses of SRB5 against EBA-CCR9 shows both a better IC50 in the depletion of CD4+CCR9+ T cells from patient blood and greater ex vivo efficacy in patient biopsies from UC and CD (Fig. 1-2). Specifically, SRB5 exhibited a 16-fold lower IC50 compared with the EBA-CCR9, indicating markedly higher potency in CCR9+ T-cell depletion (Fig. 1). The ex vivo efficacy study in 10 intestinal biopsies and matching blood showed that SRB5 treatment leads to a superior depletion of CD4+CCR9+ T cells as compared to EBACCR9, without affecting global T cell counts. More than a 50% reduction in intestine-resident CD4+ CCR9+ T cells was achieved by SRB5 treatment compared to less than 10% with EBA-CCR9. This improved efficacy of SRB5 over EBA-CCR9 was also observed in the analysis of blood samples (Fig. 2). Depletion of CCR9+ lymphocytes lead to reduced secretion of proinflammatory cytokines consistent with a shift toward a less inflamed mucosal environment and the re-establishment of mucosal immune balance. Conclusion SRB5 induces robust, selective depletion of pathogenic CCR9+ T cells and a marked reduction of key pro-inflammatory cytokines, defining a potent anti-inflammatory signature in human IBD tissue. In preclinical patient-derived head-to-head assays, SRB5 outperformed clinically advanced EBA-CCR9 through a distinct non–ligand-blocking epitope, supporting a best-in-class potential for IBD. Conflict of interest Arosa García, Laura: No conflict of interest Malvar Fernández, Beatriz: No conflicts Bastón Rey, Iria: Personal Fees: Iria Bastón Rey has received financial support for travelling and educational activities from or has served as an advisory board member for Abbvie, Johnson & Johnson, Takeda, Pfizer, Alfasigma, Ferring, Faes Farma and Otsuka Pharmaceutical and Adacyte. Ferreiro Iglesias, Rocio: RF-I has served as a speaker, or has received research or education funding from AbbVie, Takeda, MSD, Pfizer, Janssen, Adacyte, Ferring, Casen Recordati, Palex, Tillotts Pharma, Dr. Falk, Chiesi, Faes Farma, Alphasigma. Calviño Suárez, Cristina: None Porto Silva, María Del Sol: none Nieto-García, Laura: none Fernandez Poceiro, Romina: None Ucha Abal, Patricia: None De Castro Parga, Maria Luisa: I declare that I have acted as a speaker for Abbvie, Johnson & Johnson, Takeda, Tillots Pharma and Dr. Falk Pharma. I have received travel or conference attendance grants from Abbvie, Faes, Dr. Falk Pharma, Pfizer, Johnson & Johnson, Takeda, Tillots Pharma and Ferring. García Morales, Natalia: None Martínez-Cadilla, Jesús: Received honoraria from AbbVie, Takeda, and Pfizer for lectures, and support from AbbVie, Johnson & Johnson, Ferring España, and Faes Farma for congress attendance. Santamaria Casado, Ana Isabel: None Solla Gil, Elisa: None Dr. Roca Lema, Daniel: No conflict of interest Álvarez Coiradas, Elia: SunRock Biopharma employee Garrido Cuesta, Pablo: Employee of SunRock Biopharma S.L. Simón Buela, Laureano: CEO of SunRock Biopharma Hernández Ramirez, Vicente: Vicent Hernandez has served as consultant, has served as speaker, has received travel support or research funding from MSD, AbbVie, Ferring, Dr. Falk Pharma, Tillotts Pharma, Pfizer, Takeda, Janssen, KernPharma Biologics, Adacyte, Sandoz, FAES Farma, Galapagos, Lilly and Casen-Recordati Barreiro-de Acosta, Manuel: MBA has been speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Alphasigma, Lilly, Pfizer, Sandoz, Biocon, Abivax, Fresenius, Faes Farma, Ferring, Tillots, Chiesi, Adacyte, Diasorin, Oncostellae and SunRock. García Pérez, Samuel: No conflicts Conde Aranda, Javier: My research group has received funds in the past from SunRock Biopharma S.L. to study the role of novel CCR9 antibodies in the context of intestinal inflammation. We are currently collaborating with SunRock Biopharma in the realization of funded project by the Spanish Ministry of Science.
García et al. (Thu,) studied this question.