Oncology Pipeline

For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. In 2019 Lilly created Loxo Oncology at Lilly, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new medicines that work in early clinical development and will matter to patients.

CD73 Inhibitor

LY3475070

CD73 Inhibitor

Allard D, et al1; Leone RD and Emens LA2; Leone RD, et al3; Young A, et al4; Fishman P, et al5

Target
The immune system has developed multiple regulatory mechanisms to control for self-tolerance and limit tissue and organ damage during active responses to pathogens. This is partly achieved by a host of inhibitory receptors expressed on cells of the immune system that, upon activation, suppresses the inflammatory responses of immune cells. These pathways are referred to as immune checkpoints.6 In the extracellular space, the ecto-nucleotidase CD73 catalyzes the conversation of AMP to adenosine, which acts as an immune-suppressive metabolite.7 In the tumor microenvironment, tumor-derived CD73 produces extracellular adenosine that promotes tumor growth by limiting antitumor T-cell immunity via adenosine receptor signaling.8 Adenosine signals by binding to four G-protein coupled receptors: A1A, A2A, A2B, and A3.9 The most ubiquitously expressed receptor subtype on immune cells is A2A and, upon activation, exerts a suppressive effect of the inflammatory immune response by modulating CD4 and CD8+ T cells and downregulating cytokine expression.5
Molecule
LY3475070 is an oral, selective, noncompetitive inhibitor of CD73. In preclinical xenograft models, LY3475070 demonstrates reduction of adenosine in tumor tissue. In PBMCs, LY3475070 rescues adenosine-mediated suppression of T-cell proliferation and cytokine secretion.
Clinical Development
LY3475070 is being studied in a clinical trial in patients with advanced solid tumors.

References

  1. Allard D, et al. Immunol Lett. 2019;205:31-39.
  2. Leone RD, Emens LA. J Immunother Cancer. 2018;6(1):57.
  3. Leone RD, et al. Comput Struct Biotechnol J. 2018;13:265-272.
  4. Young A, et al. Cancer Discov. 2014;4(8):879-888.
  5. Fishman P, et al. Handb Exp Pharmacol. 2009;(193):399-441.
  6. Brahmer JR, Pardoll DM. Cancer Immunol Res. 2013;1(2):85-91.
  7. Horenstein AL, et al. Front Immunol. 2019;10:760.
  8. Zhang B. Cancer Res. 2010;70(16):6407-6411.
  9. Robeva AS, et al. Biochem Pharmacol. 1996;51(4):545-555.

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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