Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054

  • J Immunother Cancer. 2018 Apr 30;6(1):31. doi: 10.1186/s40425-018-0329-7.
Yiwen Li  1  2 ,  Carmine Carpenito  3 ,  George Wang  3 ,  David Surguladze  4 ,  Amelie Forest  3 ,  Maria Malabunga  3 ,  Mary Murphy  3 ,  Yiwei Zhang  5 ,  Andreas Sonyi  3 ,  Darin Chin  3 ,  Douglas Burtrum  5 ,  Ivan Inigo  4 ,  Anthony Pennello  4 ,  Leyi Shen  3 ,  Laurent Malherbe  6 ,  Xinlei Chen  7 ,  Gerald Hall  3 ,  Jaafar N Haidar  3 ,  Dale L Ludwig  5 ,  Ruslan D Novosiadly  3 ,  Michael Kalos  8  2  9
Affiliations
  • 1. 0000 0000 2220 2544grid.417540.3Lilly Research Laboratories, Department of Cancer Immunobiology New York NY USA [email protected].
  • 2. 0000 0000 2220 2544grid.417540.3Eli Lilly and Company 450 East 29th Street 10016 New York NY USA.
  • 3. 0000 0000 2220 2544grid.417540.3Lilly Research Laboratories, Department of Cancer Immunobiology New York NY USA.
  • 4. 0000 0000 2220 2544grid.417540.3Lilly Research Laboratories, Department of Preclinical Pharmacology New York NY USA.
  • 5. 0000 0000 2220 2544grid.417540.3Lilly Research Laboratories, Department of Biologics Technology New York NY USA.
  • 6. 0000 0000 2220 2544grid.417540.3Lilly Research Laboratories, Department of Non-Clinical Safety Indianapolis IN USA.
  • 7. 0000 0000 2220 2544grid.417540.3Lilly Research Laboratories, Department of Quantitative Biology New York NY USA.
  • 8. 0000 0000 2220 2544grid.417540.3Lilly Research Laboratories, Department of Cancer Immunobiology New York NY USA [email protected].
  • 9. grid.430674.2Janssen Pharmaceutical Companies of Johnson and Johnson Springhouse PA USA.
PMID: 29712568 DOI: 10.1186/s40425-018-0329-7
Abstract

Background: Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types.

Results: Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1λ monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice. LY3300054 is shown to induce primary T cell activation in vitro, increase T cell activation in combination with anti-CTLA4 antibody, and to potently enhance anti-tumor alloreactivity in several xenograft mouse tumor models with reconstituted human immune cells. High-content molecular analysis of tumor and peripheral tissues from Animals treated with LY3300054 reveals distinct adaptive immune activation signatures, and also previously not described modulation of innate immune pathways.

Conclusions: LY3300054 is currently being evaluated in phase I clinical trials for oncology indications.

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