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Sci Transl Med. 2016 Aug 24;8(353):353ra112. doi: 10.1126/scitranslmed.aaf4331.

Factor XIa-specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis.

Author information

1
Cardiovascular Research Institute, University of California, San Francisco, Room SC452P, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3122, USA.
2
Centers for Therapeutic Innovation San Francisco, Pfizer Inc., 1700 Owens Street, San Francisco, CA 94158, USA.
3
Centers for Therapeutic Innovation Boston, Pfizer Inc., 18th Floor, 3 Blackfan Circle, Boston, MA 02115, USA.
4
Pharmacokinetics, Dynamics, and Metabolism Biotherapeutics and Translational Research, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
5
Drug Safety Research and Development, Pfizer Inc., 1 Burtt Road, Andover, MA 01810, USA.
6
PMI Preclinical, 1031 Bing Street, San Carlos, CA 94070, USA.
7
Centers for Therapeutic Innovation San Francisco, Pfizer Inc., 1700 Owens Street, San Francisco, CA 94158, USA. shaun.coughlin@ucsf.edu thomas.mikita@pfizer.com.
8
Cardiovascular Research Institute, University of California, San Francisco, Room SC452P, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3122, USA. shaun.coughlin@ucsf.edu thomas.mikita@pfizer.com.

Abstract

Thrombosis is a major cause of morbidity and mortality. Current antithrombotic drugs are not ideal in that they must balance prevention of thrombosis against bleeding risk. Inhibition of coagulation factor XI (FXI) may offer an improvement over existing antithrombotic strategies by preventing some forms of thrombosis with lower bleeding risk. To permit exploration of this hypothesis in humans, we generated and characterized a series of human immunoglobulin Gs (IgGs) that blocked FXIa active-site function but did not bind FXI zymogen or other coagulation proteases. The most potent of these IgGs, C24 and DEF, inhibited clotting in whole human blood and prevented FeCl3-induced carotid artery occlusion in FXI-deficient mice reconstituted with human FXI and in thread-induced venous thrombosis in rabbits at clinically relevant doses. At doses substantially higher than those required for inhibition of intravascular thrombus formation in these models, DEF did not increase cuticle bleeding in rabbits or cause spontaneous bleeding in macaques over a 2-week study. Anticipating the desirability of a reversal agent, we also generated a human IgG that rapidly reversed DEF activity ex vivo in human plasma and in vivo in rabbits. Thus, an active site-directed FXIa-specific antibody can block thrombosis in animal models and, together with the reversal agent, may facilitate exploration of the roles of FXIa in human disease.

PMID:
27559095
DOI:
10.1126/scitranslmed.aaf4331
[Indexed for MEDLINE]

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