Submitted October 1, 2008
Accepted December 14, 2008
The impact of Fc engineering on an anti-CD19 antibody: increased Fc
receptor affinity enhances B-cell clearing in nonhuman primates
Jonathan Zalevsky*, Irene W.L. Leung, Sher Karki, Seung Y Chu, Eugene A Zhukovsky, John R Desjarlais, David F. Carmichael, and Chris E Lawrence
Xencor, Inc., Monrovia, CA, United States
* Corresponding author; email: jzalevsky{at}xencor.com.
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
receptor (FcR) binding affinity, leading to improved FcR-dependent effector cell functions and antitumor activity in murine xenografts, compared to 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, while 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 FcR 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.
