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 Blood, 16 April 2009, Vol. 113, No. 16, pp. 3735-3743.
Prepublished online as a Blood First Edition Paper on December 24, 2008; DOI 10.1182/blood-2008-10-182048.

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LYMPHOID NEOPLASIA

The impact of Fc engineering on an anti-CD19 antibody: increased Fc{gamma} receptor affinity enhances B-cell clearing in nonhuman primates

Jonathan Zalevsky1, Irene W. L. Leung1, Sher Karki1, Seung Y. Chu1, Eugene A. Zhukovsky1, John R. Desjarlais1, David F. Carmichael1, and Chris E. Lawrence1

1 Xencor, Inc, Monrovia, CA

CD19, a B cell–restricted receptor critical for B-cell development, is expressed in most B-cell malignancies. The Fc-engineered anti-CD19 antibody, XmAb5574, has enhanced Fc{gamma} receptor (Fc{gamma}R) binding affinity, leading to improved Fc{gamma}R-dependent effector cell functions and antitumor activity in murine xenografts compared with the non–Fc-engineered anti-CD19 IgG1 analog. Here, we use XmAb5574 and anti-CD19 IgG1 to further dissect effector cell functions in an immune system closely homologous to that of humans, the cynomolgus monkey. XmAb5574 infusion caused an immediate and dose-related B-cell depletion in the blood (to <10% of baseline levels) concomitant with a sustained reduction of natural killer (NK) cells. NK cells had fully recovered by day 15, whereas B-cell recovery was underway by day 57. B cells in secondary lymphoid tissues were depleted (to 34%-61% of vehicle), with involuted germinal centers apparent in the spleen. Anti-CD19 IgG1 had comparable serum exposure to XmAb5574 but demonstrated no B-cell depletion and no sustained NK-cell reduction. Thus, increasing Fc{gamma}R binding affinity dramatically increased B-cell clearing. We propose that effector cell functions, possibly those involving NK cells, mediate XmAb5574 potency in cynomolgus monkeys, and that enhancing these mechanisms should advance the treatment of B-cell malignancies in humans.


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