Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis

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BlankHuman CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to

complement-mediated cytolysis

1.. Weiguo Hu1,

2.. Xiaowen Ge1,

3.. Tao You1,

4.. Ting Xu2,

5.. Jinyan Zhang3,

6.. Gongxiong Wu1,

7.. Zhihai Peng3,

8.. Chorev1,

9.. Bertal H Aktas4,

10.. A Halperin5,

11.. R Brown6, and

12.. Xuebin Qin1,*

+ Author Affiliations

1.. 1Lab for Translational Research, Harvard Medical School

2.. 2Suzhou Industrial park, Sino Recombi Pharma

3.. 3Department of General Surgery, Shanghai First People's Hospital

4.. 4Harvard Medical School

5.. 5Lab for Translational Research, Harvard Medical School, Brigham & Women'

6.. 6Medical Oncology, Dana-Farber Cancer Institute

1.. * Corresponding Author:

Xuebin Qin, Lab for Translational Research, Harvard Medical School, One

Kendall Sqare, Building 600, 3rd Floor, Cambridge, MA, 02139, United States

xuebin_qin@...

Abstract

Rituximab efficacy in cancer therapy depends in part on induction of

complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement

regulatory protein that restricts the formation of the membrane attack complex,

thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell

non-Hodgkin's lymphoma (NHL) and up-regulation of hCD59 is an important

determinant of the sensitivity of NHL cells to rituximab treatment. Here we

report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo,

thereby sensitizing rituximab-resistant lymphoma cells and primary chronic

lymphocytic leukemia cells (CLL) to rituximab treatment. By defining PK/PD

profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely

mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing

expression levels of the complement regulators CD59 and CD55 in

rituximab-resistant cells occurs due to selection of pre-existing clones, rather

than de novo induction of these proteins. Moreover, lymphoma cells

overexpressing CD59 were directly responsible for the resistance to

rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a

therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and

CLL. Further, they suggest that preemptive elimination of CD59 overexpressing

subpopulations along with rituximab treatment may be a useful approach to ablate

or conquer rituximab resistance.