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833 CRB-601, a selective integrin αvβ8-blocking antibody, prevents TGFβ activation, promotes immune cell remodeling, and exhibits potent antitumor activity
  1. Maneesh Singh1,
  2. Daqing Wang1,
  3. Vaishali Shinde1,
  4. Danish Memon1,
  5. Rob Seed2,
  6. Jody Baron2,
  7. Stephen Nishimura2,
  8. Rachael Brake1 and
  9. Andrew Kolodziej1
  1. 1Corbus Pharmaceuticals, Inc., Norwood, MA, USA
  2. 2University of California, San Francisco, San Francisco, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background In metastatic disease, Transforming growth factor-beta (TGFβ) signaling in the tumor microenvironment (TME) is associated with immune cell exclusion, checkpoint inhibitor resistance, and poor clinical outcomes. TGFβ, produced in latent form (L-TGFβ), requires activation upon integrin binding. integrin avβ8 demonstrates exquisite specificity for L-TGFb activation. Corbus is developing a high-affinity monoclonal antibody, CRB-601, targeting integrin avβ8, which inhibits cell-bound L-TGFβ activation.

Methods Mice bearing orthotopically implanted murine breast cancer EMT6 or subcutaneously implanted murine colon carcinoma MC38 were treated with CRB-601, an anti-PD1 antibody, or the combination. CRB-601’s effects on tumor growth, immune cell populations, and biomarkers of response (e.g., TGFβ levels, cell avβ8 surface occupancy, and downregulation of SMAD2/3 phosphorylation) were evaluated. Also assessed were T-cell pharmacodynamics and memory response in the MC38 model.

Results CRB-601, as a monotherapy and in combination with anti-PD1, effectively inhibited tumor growth in both EMT6 and MC38 models. This treatment combination increased the percentage of T cells, Dendritic cells, and M1-like macrophages, suggesting a comprehensive reshaping of the TME. Biomarker analyses indicated a successful engagement with the target, integrin αvβ8, coupled with an efficient inhibition of TGFβ activation. The MC38 model demonstrated elevated levels of cytokines IL-2 and IL12p70, critical for T cell proliferation, differentiation, and activation. Furthermore, the combination therapy of CRB-601 and anti-PD1 reduced the levels of dysfunctional T cells while enriching effector T cells in the MC38 model. Mice treated with this combination therapy achieved complete remission, and the adoptive transfer of splenocytes led to enhanced anti-tumor activity.

Conclusions CRB-601 is a potent and selective integrin avβ8-blocking monoclonal antibody that can overcome tumor immune cell exclusion and enhance the activity of immune checkpoint inhibitors in vivo. The encouraging results from this study, such as tumor growth inhibition and significant immune cell infiltration, hint at the potential of CRB-601 as a promising cancer immunotherapy. Investigational New Drug (IND) enabling studies are currently underway.

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