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In vivo effects of targeting CD79b with antibodies and antibody-drug conjugates.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2009 Oct; Vol. 8 (10), pp. 2937-46. Date of Electronic Publication: 2009 Oct 06. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Amino Acid Sequence
Animals
Antibody Formation drug effects
B-Lymphocytes drug effects
B-Lymphocytes immunology
CD79 Antigens chemistry
Cell Membrane drug effects
Cell Membrane metabolism
Cross Reactions drug effects
Flow Cytometry
Humans
Immune Tolerance drug effects
Macaca fascicularis blood
Macaca fascicularis immunology
Maytansine pharmacology
Mice
Molecular Sequence Data
Spleen drug effects
Spleen immunology
Spleen pathology
Xenograft Model Antitumor Assays
Antibodies immunology
Antineoplastic Agents pharmacology
CD79 Antigens immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 8
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 19808977
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-09-0369