Anti-Extra Domain B Splice Variant of Fibronectin Antibody-Drug Conjugate Eliminates Tumors with Enhanced Efficacy When Combined with Checkpoint Blockade.

Autor:	Hooper AT; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Marquette K; Pfizer Worldwide Research, Development & Medicine, BioMedicine Design, Cambridge, Massachusetts., Chang CB; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Golas J; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Jain S; Pfizer Worldwide Research, Development & Medicine, BioMedicine Design, Cambridge, Massachusetts., Lam MH; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Guffroy M; Pfizer Worldwide Research, Development & Medicine, Drug Safety Research & Development, Pearl River, New York., Leal M; Pfizer Worldwide Research, Development & Medicine, BioMedicine Design, Cambridge, Massachusetts., Falahatpisheh H; Pfizer Worldwide Research, Development & Medicine, Drug Safety Research & Development, Pearl River, New York., Mathur D; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Chen T; Pfizer Worldwide Research, Development & Medicine, BioMedicine Design, Cambridge, Massachusetts., Kelleher K; Pfizer Worldwide Research, Development & Medicine, BioMedicine Design, Cambridge, Massachusetts., Khandke K; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Muszynska E; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Loganzo F; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Rosfjord E; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Lucas J; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Kan Z; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Subramanyam C; Pfizer Worldwide Medicinal Chemistry, Groton, Connecticut., O'Donnell C; Pfizer Worldwide Medicinal Chemistry, Groton, Connecticut., Neri D; Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland., Gerber HP; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., May C; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York., Sapra P; Pfizer Worldwide Research, Development & Medicine, Oncology Research & Development, Pearl River, New York.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2022 Sep 06; Vol. 21 (9), pp. 1462-1472.
DOI:	10.1158/1535-7163.MCT-22-0099
Abstrakt:	Extra domain B splice variant of fibronectin (EDB+FN) is an extracellular matrix protein (ECM) deposited by tumor-associated fibroblasts, and is associated with tumor growth, angiogenesis, and invasion. We hypothesized that EDB+FN is a safe and abundant target for therapeutic intervention with an antibody-drug conjugate (ADC). We describe the generation, pharmacology, mechanism of action, and safety profile of an ADC specific for EDB+FN (EDB-ADC). EDB+FN is broadly expressed in the stroma of pancreatic, non-small cell lung (NSCLC), breast, ovarian, head and neck cancers, whereas restricted in normal tissues. In patient-derived xenograft (PDX), cell-line xenograft (CLX), and mouse syngeneic tumor models, EDB-ADC, conjugated to auristatin Aur0101 through site-specific technology, demonstrated potent antitumor growth inhibition. Increased phospho-histone H3, a pharmacodynamic biomarker of response, was observed in tumor cells distal to the target site of tumor ECM after EDB-ADC treatment. EDB-ADC potentiated infiltration of immune cells, including CD3+ T lymphocytes into the tumor, providing rationale for the combination of EDB-ADC with immune checkpoint therapy. EDB-ADC and anti-PD-L1 combination in a syngeneic breast tumor model led to enhanced antitumor activity with sustained tumor regressions. In nonclinical safety studies in nonhuman primates, EDB-ADC had a well-tolerated safety profile without signs of either on-target toxicity or the off-target effects typically observed with ADCs that are conjugated through conventional conjugation methods. These data highlight the potential for EDB-ADC to specifically target the tumor microenvironment, provide robust therapeutic benefits against multiple tumor types, and enhance activity antitumor in combination with checkpoint blockade. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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