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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2211-2219.
Prepublished online as a Blood First Edition Paper on November 19, 2007; DOI 10.1182/blood-2007-08-110072.
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Submitted August 30, 2007
Accepted November 8, 2007
Bispecific anti-CD20/22 antibodies inhibit B-cell lymphoma proliferation by a unique mechanism of action
Zhengxing Qu, David. M Goldenberg*, Thomas M Cardillo, Victoria Shi, Hans J Hansen, and Chien-Hsing Chang
Research, Immunomedics, Inc., Morris Plains, NJ, United States
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, United States
* Corresponding author; email: dmg.gscancer{at}worldnet.att.net.
Combination immunotherapy with anti-CD20 and anti-CD22 mAbs shows promising activity in non-Hodgkin lymphoma. Therefore, bispecific mAbs (bsAbs) were recombinantly-constructed from veltuzumab (humanized anti-CD20) and epratuzumab (humanized anti-CD22) and evaluated in vitro and in vivo. While none of the parental mAbs alone or mixed had notable anti-proliferative activity against Burkitt lymphoma cells when not crosslinked, the bsAbs [e.g., anti-CD20 IgG-anti-CD22 (scFv)2] were inhibitory without crosslinking and synergistic with B-cell antigen (BCR)-mediated inhibition. The bsAbs demonstrated higher ADCC activity than the parental mAbs, but not CDC of the parental CD20 mAb. Crosslinking both CD20 and CD22 with the bsAbs resulted in the prominent redistribution of not only CD20 but also CD22 and BCR into lipid rafts. Surprisingly, appreciable translocation of CD22 into lipid rafts was also observed after treatment with epratuzumab. Finally, the bsAbs inhibited Daudi lymphoma transplant growth, but showed a significant advantage over the parental anti-CD20 mAb only at the highest dose tested. These results suggest that recombinantly-fused, complementary, bispecific, anti-CD20/22 antibodies exhibit functional features distinct from their parental antibodies, perhaps representing new candidate therapeutic molecules.
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