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CD73 monoclonal antibody

JAB-BX102 is a humanized anti-CD73 monoclonal antibody (mAb)developed by Jacobio to inhibit the enzymatic activity of CD73. CD73 is the key node of adenosine pathway, and its inhibitors have broad therapeutic prospects for tumors dependent on adenosine pathway. Relevant studies have shown that adenosine promotes SHP2 phosphorylation, suggesting that anti-CD73 antibody can be combined with SHP2 inhibitor, which is also developed by Jacobio to benefit patients with advanced solid tumors.

Jacobio has received IND (Investigational New Drug) approval of anti-CD73 mAb JAB-BX102 from the Food and Drug Administration (FDA) of the United States on Oct 15 2021, Jacobio plans to initiate a Phase I/IIa clinical trial in patients with solid tumors.

Mechanism of Action

CD73, also known as ecto-5'-nucleotidase, or Ecto5’NTase, is a membrane-bound/free protein, which can hydrolyze AMP to adenosine. Adenosine inhibits tumor immune response after interacting with P1 receptor on cell surface. CD73 is highly expressed and associated with poor prognosis in various tumor tissues, such as gastric cancer, renal cell carcinoma, prostate cancer, triple negative breast cancer, and non-small cell adenocarcinoma.

JAB-BX102 specifically binds to CD73 and blocks its extracellular 5'-nucleotidase activity. By reducing the production of adenosine, JAB-BX102 can relieve the inhibitory effect of adenosine on the proliferation and tumor-killing activity of CD8+ T cells, and weaken the stimulation of adenosine on immunosuppressive cells, so as to modulate the tumor microenvironment and enhance the anti-tumor immune response. Tumor immunotherapy represented by PD-(L)1 antibody can effectively and persistently inhibit tumor growth with less adverse effects. However, the response rate of PD-(L)1 antibody is limited, and the activation of adenosine pathway may be one of the important reasons of resistance. Therefore, inhibiting the activity of CD73 may be an effective combination strategy to improve the efficacy of PD-(L)1 antibody.

Indications
CD73 is over-expressed in many malignant tumors, including melanoma, triple negative breast cancer, non-small cell lung cancer, renal cell carcinoma, bladder cancer, prostate cancer, gastric cancer, colorectal cancer, ovarian cancer and malignant glioma. The preliminary clinical results of other CD73 inhibitors suggest that it has potential clinical efficacy in non-small cell lung cancer, triple negative breast cancer, renal cell carcinoma and other solid tumors.
 
Clinical Trials
Asset Programs Region Phase Indication
JAB-BX102 Mono United States I/IIa Solid tumor
Monotherapy Combo w/ PD-1 mAb
Reference
  1. Turiello, R., Pinto, A., and Morello, S. (2020). CD73: A Promising Biomarker in Cancer Patients. Front Pharmacol 11, 609931.
  2. Neo, S. Y., Yang, Y., Record, J., Ma, R., Chen, X., Chen, Z., Tobin, N. P., Blake, E., Seitz, C., Thomas, R., et al. (2020). CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment. J Clin Invest 130, 1185-1198.
  3. Harvey, J. B., Phan, L. H., Villarreal, O. E., and Bowser, J. L. (2020). CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers. Front Immunol 11, 508.
  4. Vijayan, D., Young, A., Teng, M. W. L., and Smyth, M. J. (2017). Targeting immunosuppressive adenosine in cancer. Nature reviews Cancer 17, 709-724.
  5. Zhang, H., Conrad, D. M., Butler, J. J., Zhao, C., Blay, J., and Hoskin, D. W. (2004). Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases. J Immunol 173, 932-944.