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CCR9 prueba
Chemokine receptor 9 (CCR9) is a G protein–coupled receptor involved in the regulation of immune cell trafficking, particularly directing lymphocyte homing to the intestinal tract through its interaction with the ligand CCL25. While its physiological expression is largely restricted to the thymus and small intestine, aberrant activation of the CCR9/CCL25 axis has been implicated in multiple pathological conditions.
In immune-mediated diseases such as inflammatory bowel disease (IBD), CCR9 drives the recruitment of pathogenic lymphocytes to inflamed intestinal tissues, contributing to chronic inflammation and fibrosis. In parallel, CCR9 is frequently overexpressed in both solid and hematologic malignancies, where it promotes tumor progression, metastatic dissemination, and resistance to therapy.
Together, these roles position CCR9 as a compelling therapeutic target across oncology and inflammatory diseases.
CCR9 Programs. Scientific Evidence
CCR9 IN IBD
- CCR9 plays a central role in immune-mediated diseases, particularly in inflammatory bowel disease (IBD), where it regulates the selective migration of lymphocytes to the intestinal tract.
- Its ligand, CCL25, is normally expressed in the small intestine but not in the colon under non-inflammatory conditions. However, in inflammatory bowel disease (IBD), dysregulation of the CCR9/CCL25 axis has been associated with intestinal inflammation and disease activity, supporting its role in the recruitment of pathogenic lymphocytes to affected intestinal tissue.Clinical studies further support this axis, showing increased numbers of circulating CCR9⁺ T cells in patients with intestinal inflammation.
- Beyond inflammation, the CCR9/CCL25 pathway has also been implicated in fibrotic processes. Elevated expression of both CCR9 and CCL25 has been observed in gut biopsies from patients with ulcerative colitis and Crohn’s disease (CD), particularly in those with stricturing disease, a severe complication with significant clinical impact and limited therapeutic options.
CCR9 IN ONCOLOGY
Solid tumors
- CCR9 overexpression has emerged as a key driver of tumor progression in solid malignancies, where it is strongly associated with increased metastatic potential and resistance to therapy, partly mediated through activation of the PI3K/Akt signaling pathway.
- In pancreatic ductal adenocarcinoma (PDAC), more than 70% of patients exhibit elevated CCR9 expression, which correlates with a higher incidence of early metastatic spread. Similarly, CCR9 upregulation has been linked to chemoresistance in ovarian cancer models, reinforcing its role in treatment failure.
- In lung cancer, patient’s data suggest that CCR9 expression is associated with more advanced disease stages and lymph node metastasis, supporting its potential relevance as a tumor-selective therapeutic target.
Hematologic tumors
- In hematologic malignancies, CCR9 is frequently overexpressed and has been associated with disease initiation and progression, particularly in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML).
- T-ALL, an orphan disease accounting for 15–25% of ALL cases, remains a significant clinical challenge, especially in the relapsed setting where mortality is high. Notably, CCR9 is overexpressed in up to 80% of T-ALL patients, supporting its relevance as a therapeutic target.
Anti-CCR9 Therapeutic Antibodies
SunRock has developed an anti-CCR9 humanized antibody with increased Antibody-dependent cellular cytotoxicity (ADCC), SRB5, for the depletion of CCR9+ T cells in the context of IBD. Efficacy has been proven in vitro, in vivo and ex vivo in intestinal biopsies from IBD patients.
SunRock has also developed SRB123, a first-in-class anti-CCR9 antibody-drug conjugate (ADC) designed to selectively target and eliminate CCR9⁺ tumor cells. Conjugated to a next-generation topoisomerase I inhibitor payload, SRB123 has demonstrated potent and selective cytotoxic activity in vitro and robust antitumor efficacy in vivo across multiple preclinical cancer models.
SunRock Biopharma owns exclusive, world-wide rights of the IP protecting the CCR9-targeted antibodies.
SunRock’s lead asset, SRB5, is a best-in-class anti-CCR9 antibody that shows a MoA based on ADCC and demonstrated depletion of circulating and intestinal CCR9 expressing T cells both in vivo and ex vivo in patient samples
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SRB5 showed ex vivo efficacy in intestinal explants from IBD patients
- SRB5 treatment specifically reduces the percentage of CCR9⁺ T lymphocyte subsets in peripheral blood, without affecting the overall number of circulating T lymphocytes
- SRB5 demonstrates therapeutic efficacy in IBD patients regardless of clinical history, showing positive outcomes even in those naïve, or even treated with mesalazine, infliximab, Ustekinumab or JAK inhibitors.
- SRB5-mediated depletion of CD4+ CCR9+ T cells is associated with a significant reduction in the soluble levels of the main proinflammatory cytokines
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SRB5 showed improved binding, ADCC activity and efficacy compared to benchmark anti-CCR9 antibody
- SRB5 shows a 16-fold higher CCR9+ T cell-depleting activity compared with benchmark anti-CCR9 antibody
- SRB5 display sub-nanomolar binding, achieving markedly higher target occupancy than benchmark anti-CCR9 antibody
- In patient-derived assays, SRB5 shows greater efficacy than benchmark anti-CCR9 antibody in depleting CCR9⁺ CD4⁺ T cells both in intestinal explants and in peripheral blood
- No toxicity symptoms in any of the animal models tested
SunRock is co-developing SRB123, with Escugen Biotechnology. SRB123 is a first-in-class CCR9 targeting ADC with optimized efficacy and safety
Escugen’s EZWi-Fit® Technology Platform employs stable-cleavable linkers and an innovative Topoisomerase I inhibitor payload, showing outstanding antitumor efficacy and safety profile supporting its best-in-class potential
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SRB123 favorable safety profile in mice at both DAR4 and DAR8
- A repeat-dose toxicity study in huCCR9 knock-in mice showed that SRB123 DAR4 and DAR8 were well tolerated.
- No clinical signs of toxicity were observed, and body weight remained stable and comparable to vehicle-treated animals.
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SRB123 efficacy in Ovarian and Pancreatic PDX Models
- SRB123 induced complete tumor regression in a highly aggressive HGSOC PDX model derived from ascitic-fluid organoids from a patient with stage IVB disease who was refractory to carboplatin/paclitaxel and rapidly progressed.
- In pancreatic cancer PDX models, SRB123 achieved tumor stasis in a multidrug-resistant model refractory to gemcitabine/Abraxane, and tumor regression in a second model, showing clear superiority over gemcitabine/Abraxane.
Anti-CCR9 Pipeline
SRB5
Discovery
Preclinical
Clinic phases
SRB123
Discovery
Preclinical
Clinic phases
