Milatuzumab is a humanized monoclonal antibody targeting tumors that express the CD74 antigen. It is the first anti-CD74 antibody that has entered into human testing and is currently being studied for the treatment of multiple myeloma, non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Milatuzumab has received orphan drug designation from the Food and Drug Administration in the United States for the treatment of multiple myeloma and chronic lymphocytic leukemia.
CD74 is present on a variety of hematological tumors and even on some solid cancers, with restricted expression by normal tissues. It is an attractive target for a drug conjugate because of its rapid internalizing property. In preclinical studies, both naked Milatuzumab and Milatuzumab conjugated with doxorubicin have demonstrated anti-lymphoma activity in-vivo.
Milatuzumab, as a doxorubicin conjugate, is currently in a Phase I/II clinical trial for the treatment of patients with relapsed multiple myeloma. More information on this trial can be accessed at clinicaltrials.gov. This is the first agent from our antibody-drug conjugate program that has entered into human testing. We completed an initial Phase I study of naked Milatuzumab in 24 patients with relapsed multiple myeloma. Results from this study were presented at the 2009 annual meeting of the American Society of Clinical Oncology.
Non-Hodgkin’s Lymphoma/Chronic Lymphocytic Leukemia
Weill-Cornell Medical Center in New York is currently conducting a Phase I study in patients with recurrent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL), who have progressed after at least one prior standard treatment, with Milatuzumab. This clinical study is funded in part by a grant to Weill-Cornell Medical from the National Cancer Institute.
We are also conducting a clinical trial in patients with CLL using different doses and dosing schedules of Milatuzumab. clinicaltrials.gov
The James Cancer Hospital and Solove Research Institute, a National Cancer Institute-designated comprehensive cancer center at The Ohio State University, is exploring possible synergy between Milatuzumab with Veltuzumab. Preliminary results from their Phase I/II study in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma were presented at the 2010 annual meeting of the American Society of Hematology.
Combination anti-CD74 (Milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma. L. Alinari, B. Yu, B.A. Christian, F. Yan, J. Shin, R. Lapalombella, E. Hertlein, M.E. Lustberg, C. Quinion, X. Zhang, G. Lozanski, N. Muthusamy, M. Praetorius-Ibba, O.A. O'Connor, D.M. Goldenberg, J.C. Byrd, K.A. Blum, R.A. Baiocchi. Blood 117:4530-4541, 2011.
A Phase I study of Milatuzumab, a humanized anti-CD74 antibody, and Veltuzumab, a humanized anti-CD20 antibody, in patients with relapsed and refractory B-cell non-Hodgkin's lymphoma. B. Christian, L. Alinari, C.T. Earl, E. Wilding, C. Quinion, M. Lustberg, D.M. Benson, Jr., J.A. Jones, J.C. Byrd, W.A. Wegener, D.M. Goldenberg, R.A. Baiocchi, K.A. Blum. Blood 116:Abstract 2788, 2010.
TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner. I. Binsky, F. Lantner, V. Grabovsky, N. Harpaz, L. Shvidel, A. Berrebi, D.M. Goldenberg, L. Leng, R. Bucala, R. Alon, M. Haran, I. Shachar. J Immunol 184:4761-4769, 2010.
Dose-escalation trial of Milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma. J.L. Kaufman, R. Niesvizky, E.A. Stadtmauer, A. Chanan-Khan, D. Siegel, H. Horne, N. Teoh, W. A. Wegener, D. M. Goldenberg. J Clin Oncol 27:15s (suppl; abstr 8593), 2009.
CD74: a new candidate target for the immunotherapy of B-cell neoplasms. R. Stein, M.J. Mattes, T.M. Cardillo, H.J. Hansen, C.H. Chang, J. Burton, S. Govindan, D.M. Goldenberg. Clin Cancer Res 13:5556s-5563s, 2007.
IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic Lymphocytic leukemia survival. I. Binsky, M. Haran, D. Starlets, Y. Gore, F. Lantner, N. Harpaz, L. Leng, D.M. Goldenberg, L. Shvidel, A. Berrebi, R. Bucala, I. Shachar. Proc Natl Acad Sci USA. 104:13408-13413, 2007.
Combining Milatuzumab with bortezomib, doxorubicin, or dexamethasone improves responses in multiple myeloma cell lines. R. Stein, M.R. Smith, S. Chen, M. Zalath, D.M. Goldenberg. Clin Cancer Res 15:2808-2817, 2009.
Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys. P. Sapra, R. Stein, J. Pickett, Z. Qu, S.V. Govindan, T.M. Cardillo, H.J. Hansen, I.D. Horak, G.L. Griffiths, D.M. Goldenberg. Clin Cancer Res 11:5257-5264, 2005.