Milatuzumab

Milatuzumab (or hLL1) is an anti-CD74[1] humanized monoclonal antibody for the treatment of multiple myeloma non-Hodgkin's lymphoma and chronic lymphocytic leukemia.[2][3][4][5]

Milatuzumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD74
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6518H10066N1758O2020S40
Molar mass146658.91 g·mol−1
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The drug is the first anti-CD74 antibody that has entered into human testing and is currently being studied for the treatment of multiple myeloma. 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.

Milatuzumab was developed by Immunomedics, Inc, (Morris Plains NJ USA).

CD74

CD74 is present on a variety of hematological tumors and even on some solid cancers. It is present in limited amounts in normal tissues but widely found in leukemias, lymphomas and the vast majority of multiple myeloma cases. CD74 is involved in a cell-to-cell communication pathway that is critical for survival. When CD74 is blocked by milatuzumab, it can lead to cell death.

CD74 is an attractive target for a drug conjugate because of its rapid internalizing property.

In preclinical studies with human lymphomas and myelomas, both naked Milatuzumab and the Milatuzumab conjugated with doxorubicin,[6] an antibody-drug conjugate or ADC, have demonstrated anti-lymphoma activity in-vivo.

Antibody-drug Conjugates

IMMU-110
hLL1-Dox
Milatuzumab has been linked to doxorubicin to form an antibody-drug conjugate or ADC (known as hLL1-Dox or IMMU-110) for treatment of relapsed multiple myeloma. A phase I/II clinical trial has started (in 2010).[7][8] This open-label, multi-center Phase I/II study aims to evaluate the safety and tolerability of milatuzumab-doxorubicin conjugate in patients with recurrent or refractory multiple myeloma, and to obtain preliminary information on efficacy, pharmacokinetics, and immunogenicity. The ADC will be administered intravenously on days 1, 4, 8, & 11 every 21 days for up to 8 treatment cycles. Four different dose levels of the doxorubicin conjugate of milatuzumab will be studied in groups of 3-6 patients. Once an optimal dose has been found, up to an additional 30 patients will be studied at that dose level. The study is due to complete in July 2013[9] As of June 2016 no results seem to have been published or announced.

References
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Milatuzumab-Doxorubicin (IMMU-110 / hLL1-dox) Clinical Trials - ADC Review / Journal of Antibody-drug Conjugates
  8. Immunomedics initiates dosing in milatuzumab-doxorubicin conjugate Phase I/II trial for relapsed multiple myeloma - News Medical and Immunomedics Press Release. |date=16 June 2010
  9. A Study of hLL1-DOX (Milatuzumab-Doxorubicin Antibody-Drug Conjugate) in Patients With Multiple Myeloma. Clinical Trials
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