In vivo effects of targeting CD79b with antibodies and antibody-drug conjugates.
Antibodies directed against B cells are in use for the treatment of non-Hodgkin's lymphoma and autoimmune disorders. The B-cell-restricted surface antigen CD79b, a signaling component of the B-cell receptor, has been shown as a promising antibody target in mouse efficacy models of systemic lupus erythematosus. Anti-CD79b antibody-drug conjugates (ADC), cytotoxic drugs linked through specialized chemical linkers to antibodies, are effective in mouse xenograft models of non-Hodgkin's lymphoma. We were interested in evaluating the systemic effects of anti-CD79b antibodies and ADCs in normal animals as a step toward the development of these molecules as therapeutics. As we were unable to identify any cell surface binding anti-human CD79b antibodies that were cross-reactive to other species, we developed an antibody to cynomolgus monkey (Macaca fascicularis) CD79b (anti-cyCD79b). The anti-cynomolgus antibody, anti-cyCD79b (10D10), and the maytansine (tubulin inhibitor)-conjugated ADC, anti-cyCD79b (10D10)-MCC-DM1, were administered to cynomolgus monkeys at approximately 30 mg/kg (6,000 microg DM1/m(2)) for two doses 3 weeks apart. Anti-cyCD79b and anti-cyCD79b-MCC-DM1 resulted in peripheral blood B-cell depletion of approximately 65% and approximately 94%, respectively. In addition, anti-cyCD79b-MCC-DM1 resulted in near-complete absence of splenic germinal centers, an observation supporting an effect on dividing B cells. Both molecules were well tolerated, with minimal findings for the antibody and findings for the ADC limited to the lymphoid and hematopoietic systems, liver, and peripheral nerves. These preclinical data suggest that targeting CD79b with antibodies or ADCs may provide safe and effective therapies for B-cell malignancies and autoimmune diseases.
Zheng
Bing
B
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Fuji
Reina N
RN
Elkins
Kristi
K
Yu
Shang-Fan
SF
Fuh
Franklin K
FK
Chuh
Josefa
J
Tan
Christine
C
Hongo
Jo-Anne
JA
Raab
Helga
H
Kozak
Katherine R
KR
Williams
Marna
M
McDorman
Elena
E
Eaton
Dan
D
Ebens
Allen
A
Polson
Andrew G
AG
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051925:CD79 Antigens / Q000737:chemistry / Q000276:immunology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003429:Cross Reactions / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008252:Macaca fascicularis / Q000097:blood / Q000276:immunology; D008453:Maytansine / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000970:Antineoplastic Agents; D051925:CD79 Antigens; D008453:Maytansine