Oncotarget

Research Papers:

Distinct mobilization of leukocytes and hematopoietic stem cells by CXCR4 peptide antagonist LY2510924 and monoclonal antibody LY2624587

Sheng-Bin Peng _, Robert D. Van Horn, Tinggui Yin, Robin M. Brown, William C. Roell, Victor H. Obungu, Charles Ruegg, Victor J. Wroblewski, Eyas Raddad and John R. Stille

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Oncotarget. 2017; 8:94619-94634. https://doi.org/10.18632/oncotarget.21816

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Abstract

Sheng-Bin Peng1, Robert D. Van Horn1, Tinggui Yin1, Robin M. Brown1, William C. Roell1, Victor H. Obungu1, Charles Ruegg2, Victor J. Wroblewski1, Eyas Raddad2 and John R. Stille2

1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA

2The Chorus Group, Eli Lilly and Company, Indianapolis, Indiana 46285, USA

Correspondence to:

Sheng-Bin Peng, email: peng_sheng-bin@lilly.com

Keywords: CXCR4, peptide antagonist, LY2510924, monoclonal antibody, LY2624587

Received: June 22, 2017     Accepted: September 15, 2017     Published: October 10, 2017

ABSTRACT

Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 play a critical role in mobilization and redistribution of immune cells and hematopoietic stem cells (HSCs). We evaluated effects of two CXCR4-targeting agents, peptide antagonist LY2510924 and monoclonal antibody LY2624587, on mobilizing HSCs and white blood cells (WBCs) in humans, monkeys, and mice. Biochemical analysis showed LY2510924 peptide blocked SDF-1/CXCR4 binding in all three species; LY2624587 antibody blocked binding in human and monkey, with minimal activity in mouse. Cellular analysis showed LY2624587 antibody, but not LY2510924 peptide, down-regulated cell surface CXCR4 and induced hematological tumor cell death; both agents have been shown to inhibit SDF-1/CXCR4 interaction and downstream signaling. In animal models, LY2510924 peptide induced robust, prolonged, dose- and time-dependent WBC and HSC increases in mice and monkeys, whereas LY2624587 antibody induced only moderate, transient increases in monkeys. In clinical trials, similar pharmacodynamic effects were observed in patients with advanced cancer: LY2510924 peptide induced sustained WBC and HSC increases, while LY2624587 antibody induced only minimal, transient WBC changes. These distinct pharmacodynamic effects in two different classes of CXCR4 inhibitors are clinically important and should be carefully considered when designing combination studies with immune checkpoint inhibitors or other agents for cancer therapy.


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