2. Academic Validation
  3. Discovery and Characterization of a First-in-Class LIV1-TLR7/8 Immunomodulatory Conjugate with Robust Myeloid Activation and Antitumor Activity

Discovery and Characterization of a First-in-Class LIV1-TLR7/8 Immunomodulatory Conjugate with Robust Myeloid Activation and Antitumor Activity

  • J Med Chem. 2025 Jun 12;68(11):11322-11339. doi: 10.1021/acs.jmedchem.5c00264.
Sayumi Yamazoe 1,  Yam Poudel 1,  Emanuela Sega 1,  Anandaroop Mukhopadhyay 1,  Radha Ramakrishnan 2,  Okechukwu Ukairo 3,  Scot Liu 1,  Rahima Akter 1,  Keerthi Sadanala 1,  Kathryn Que 1,  Qinqin Cheng 1,  Srikanth Kotapati 1,  Madhura Deshpande 1,  Matthew Cox 1,  Shishir Chourey 2,  Anuradha Gupta 4,  James Kempson 5,  Kumar Pabbisetty 4,  Mahammed Kaspady 4,  Debabrata Bhattasali 4,  Shiuhang Yip 4,  Dauh-Rurng Wu 4,  Deepa Pookot 1,  Yvonne Li 1,  Alexander Kozhich 5,  Dieter Drexler 3,  Stephen Carl 5,  Ekaterina Deyanova 5,  Michael Smith 5,  Henry Chan 2,  Sean West 1,  S J Diong 1,  Aram Chang 1,  Lore Florin 1,  Arvind Mathur 5,  Pavel Strop 1,  Christoph W Zapf 2,  Deborah Law 1,  Nicholas Wilson 1,  Miranda Broz 1,  Eugene P Chekler 1
Affiliations

Affiliations

  • 1 Bristol Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
  • 2 Bristol Myers Squibb Research & Development, 10300 Campus Point Drive, San Diego, California 92121, United States.
  • 3 Bristol Myers Squibb Research & Development, 250 Water Street, Cambridge, Massachusetts 02141, United States.
  • 4 The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.
  • 5 Bristol Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
PMID: 40411528 DOI: 10.1021/acs.jmedchem.5c00264
Abstract

Herein, we describe the discovery of a novel immunostimulatory drug conjugate (IMC) that employs TLR7/8 agonists conjugated to a tumor-targeting LIV1 antibody. Targeting TLR7/8 agonists to LIV1-expressing tumors enables localized delivery, thereby minimizing systemic toxicity while promoting inflammation and T cell recruitment within the tumor microenvironment (TME) for enhanced antitumor efficacy. Dual activation of TLR7 and TLR8 within the TME facilitates the recruitment of diverse immune cells and induces a broad spectrum of pro-inflammatory cytokines, effectively reshaping the immunosuppressive TME by upregulating costimulatory molecules. The mechanism of action of the IMC involves tumor recognition via surface antigens and Fcγ-mediated phagocytosis, followed by activation of myeloid cells to efficiently present tumor antigens to T-cells, thereby eliciting antitumor immunity. The designed IMCs demonstrate the ability to activate myeloid cells in the presence of tumor cells, display robust antitumor activity, and are well tolerated in toxicology studies.

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