Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma.
Targeting cytotoxic drugs to cancer cells using antibody-drug conjugates (ADCs), particularly those with stable linkers between the drug and the antibody, could be an effective cancer treatment with low toxicity. However, for stable-linker ADCs to be effective, they must be internalized and degraded, limiting potential targets to surface antigens that are trafficked to lysosomes. CD79a and CD79b comprise the hetrodimeric signaling component of the B-cell receptor, and are attractive targets for the use of ADCs because they are B-cell-specific, expressed in non-Hodgkin lymphomas (NHL), and are trafficked to a lysosomal-like compartment as part of antigen presentation. We show here that the stable-linker ADCs anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are capable of target-dependent killing of nonHodgkin lymphoma cell lines in vitro. Further, these 2 ADCs are equally effective as low doses in xenograft models of follicular, mantle cell, and Burkitt lymphomas, even though several of these cell lines express relatively low levels of CD79b in vivo. In addition, we demonstrate that anti-CD79b ADCs were more effective than anti-CD79a ADCs and that, as hypothesized, anti-CD79b antibodies downregulated surface B-cell receptor and were trafficked to the lysosomal-like major histocompatibility complex class II-positive compartment MIIC. These results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are promising therapeutics for the treatment of NHL.
Polson
Andrew G
AG
Department of Translational Oncology, Genentech, South San Francisco, CA, USA. polson@gene.com
Yu
Shang-Fan
SF
Elkins
Kristi
K
Zheng
Bing
B
Clark
Suzanna
S
Ingle
Gladys S
GS
Slaga
Dionysos S
DS
Giere
Lynne
L
Du
Changchun
C
Tan
Christine
C
Hongo
Jo-Anne
JA
Gogineni
Alvin
A
Cole
Mary J
MJ
Vandlen
Richard
R
Stephan
Jean-Philippe
JP
Young
Judy
J
Chang
Wesley
W
Scales
Suzie J
SJ
Ross
Sarajane
S
Eaton
Dan
D
Ebens
Allen
A
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D051925:CD79 Antigens / Q000276:immunology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005434:Flow Cytometry; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D014183:Transplantation, Heterologous
D000906:Antibodies; D051925:CD79 Antigens; D006681:HLA-D Antigens; D018796:Immunoconjugates; D011947:Receptors, Antigen, B-Cell