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Protein Design Labs, Inc., Mountain View, CA 94043
E- and P-selectin (CD62E and CD62P) are cell adhesion molecules
that mediate leukocyte-endothelial cell and leukocyte-platelet
interactions and are involved in leukocyte recruitment during
inflammation. We previously developed a murine mAb, EP-5C7 (or
mEP-5C7), that binds and blocks both E- and P-selectin. When used in
humans, murine mAbs have short circulating half-lives and generally
induce potent human anti-mouse Ab responses. We therefore
engineered a humanized, complementarity determining region-grafted
version of mEP-5C7 incorporating human 
4 heavy and 
light chain
constant regions (HuEP5C7.g4). HuEP5C7.g4 retains the specificity and
avidity of mEP-5C7, binding to human E- and P-selectin but not to human
L-selectin, and blocking E- and P-selectin-mediated adhesion.
Surprisingly, when administered to rhesus monkeys, HuEP5C7.g4 was
eliminated from the circulation very rapidly, even faster than the
original murine Ab. To isolate the cause of the short serum half-life
of HuEP5C7.g4, several Ab variants were constructed. A chimeric IgG4 Ab
was made by replacing the humanized V regions with murine V regions. A
humanized IgG2 Ab, HuEP5C7.g2, was also made by replacing the human
4 with a 2 constant region. Results from pharmacokinetic studies
in rhesus monkeys demonstrated that the chimeric IgG4 is also rapidly
eliminated rapidly from serum, similar to the humanized IgG4 Ab, while
the humanized IgG2 Ab displays a long circulation half-life, typical of
human Abs.
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  J. Mocco, T. Choudhri, J. Huang, E. Harfeldt, L. Efros, C. Klingbeil, V. Vexler, W. Hall, Y. Zhang, W. Mack, et al. HuEP5C7 as a Humanized Monoclonal Anti-E/P-Selectin Neurovascular Protective Strategy in a Blinded Placebo-Controlled Trial of Nonhuman Primate Stroke Circ. Res., November 15, 2002; 91(10): 907 - 914. [Abstract] [Full Text] [PDF]
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 J. Melrose, N. Tsurushita, G. Liu, and E. L. Berg IFN-{gamma} Inhibits Activation-Induced Expression of E- and P-Selectin on Endothelial Cells J. Immunol., September 1, 1998; 161(5): 2457 - 2464. [Abstract] [Full Text] [PDF]
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 K. Konstantopoulos, S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, et al. Venous Levels of Shear Support Neutrophil-Platelet Adhesion and Neutrophil Aggregation in Blood via P-Selectin and ß2-Integrin Circulation, September 1, 1998; 98(9): 873 - 882. [Abstract] [Full Text] [PDF]
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