Immunomedics announced results from 3 preclinical studies aimed at understanding the mechanism of action of its proprietary humanized anti-CD74 antibody, milatuzumab, which is currently in clinical development for multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL)
NEW ORLEANS, LA, USA | December 7, 2009 | Immunomedics, Inc. (Nasdaq:IMMU – News), a biopharmaceutical company focused on developing monoclonal antibodies to treat cancer and other serious diseases, today at the 51st annual meeting of the American Society of Hematology announced results from 3 preclinical studies aimed at understanding the mechanism of action of its proprietary humanized anti-CD74 antibody, milatuzumab, which is currently in clinical development for multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
The first study was on CLL, a progressive disease for which most patients require treatment. A team of researchers at the Ohio State University, Columbus, OH, led by Dr. John Byrd, demonstrated expression of CD74 on the surface of CLL cells, but no expression was found on T cells. Milatuzumab-induced cell death occurred very rapidly, with 57% cell survival at 4 hours and only 30% at 24 hours, which was superior to that observed with rituximab.
The mode of cell death induced by milatuzumab was found to be mediated directly through interaction with CD74 and its ensuing effects on signal transduction. Milatuzumab, when crosslinked, promotes the maintenance of CD74 on the cell surface and thereby prevents receptor internalization and subsequent signaling. Retention of the CD74 receptor on the surface of B cells can also be induced, without the presence of a crosslinking antibody, the investigators found, by incorporating milatuzumab into liposomes.
The subject of the second study was mantle cell lymphoma (MCL), an incurable B-cell malignancy with limited therapeutic options. Despite the success of rituximab in treating B-cell lymphoma, its use as a single agent or in combination with chemotherapy in MCL has demonstrated modest activity. Since rituximab and milatuzumab target distinct antigens lacking known association, Dr. Byrd and his team at the Ohio State University, explored a combination strategy with these antibodies in MCL cell lines, patient samples, and in a preclinical model.
Primary tumor cells from MCL patients and 6 different MCL cell lines with variable levels of CD74 expression were used in this study. The combination of milatuzumab and rituximab was able to induce enhanced cell death in all MCL cell lines and MCL primary cells, regardless of antigen density. Moreover, milatuzumab-induced MCL cell death was found to be dependent on actin polymerization and inhibition of NF-kB, a protein complex that controls the transcription of DNA.
The in-vivo activity of rituximab and milatuzumab was examined in a preclinical model of human MCL in mice, with survival as the primary end-point. The mean survival for the combination-treated group was 44.5 days, compared to 28 days for the group of mice treated with trastuzumab, a non-CD74 binding antibody, 33.5 days and 38 days for the milatuzumab-treated and rituximab-treated mice, respectively. Thus, the combination treatment prolonged survival providing justification for further evaluation of milatuzumab and rituximab in combination in MCL, according to the authors.
The third study, presented by Dr. Xiaochuan Chen of the Garden State Cancer Center, Belleville, NJ, assessed the binding profiles and functional effects of milatuzumab on human antigen-presenting cells (APC). Because CD74 is expressed in normal B cells, monocytes, macrophages, Langerhans cells, follicular and blood dendritic cells, the goal of this study was to evaluate if milatuzumab is toxic to or affects the function of these immune cells. In addition, binding and cytotoxicity on a panel of leukemia/lymphoma cell lines and CLL patient cells were tested to demonstrate the range of malignancies that can be treated with this antibody.
In correlation with the levels of CD74 expression, milatuzumab bound efficiently to different subsets of blood dendritic cells (DC), B lymphocytes, monocytes, and immature DCs derived from human monocytes in vitro, but not LPS-matured DCs. For malignant B cells, milatuzumab bound to the surface of 2/3 acute myeloid leukemia (AML), 2/2 MCL, 4/4 acute lymphoblastic leukemia (ALL), 1/1 hairy cell leukemia, 2/2 CLL, 7/7 NHL, and 5/6 MM cell lines, as well as cells of 4/6 CLL patient specimens.
Following incubation with milatuzumab, significant cytotoxicity was observed in 2/2 MCL, 2/2 CLL, 3/4 ALL, 1/1 hairy cell, 2/2 NHL, and 2/2 MM cell lines, and 3/4 CD74-positive CLL patient cells, but not in the AML cell lines. In contrast, milatuzumab had minimal effects on the viability of DCs or B cells that normally express CD74. Moreover, milatuzumab treatment did not alter DC maturation and DC-mediated T-cell functions, nor did it influence antigen presentation or cross-presentation.
We believe these results demonstrate that milatuzumab is a highly specific therapeutic antibody against B-cell malignancies with potentially minimal side effects. It also suggests that milatuzumab may be a promising novel delivery vehicle for in-vivo targeted vaccinations, given its efficient binding, but lack of cytotoxicity and functional disruption on CD74-expressing normal APCs.
These studies were supported in part by grants from the National Institutes of Health.
About Immunomedics
Immunomedics is a New Jersey-based biopharmaceutical company primarily focused on the development of monoclonal, antibody-based products for the targeted treatment of cancer, autoimmune and other serious diseases. We have developed a number of advanced proprietary technologies that allow us to create humanized antibodies that can be used either alone in unlabeled or "naked" form, or conjugated with radioactive isotopes, chemotherapeutics or toxins, in each case to create highly targeted agents. Using these technologies, we have built a pipeline of therapeutic product candidates that utilize several different mechanisms of action. We also have a majority ownership in IBC Pharmaceuticals, Inc., which is developing a novel Dock-and-Lock (DNL) methodology with us for making fusion proteins and multifunctional antibodies, and a new method of delivering imaging and therapeutic agents selectively to disease, especially different solid cancers (colorectal, lung, pancreas, etc.), by proprietary, antibody-based, pretargeting methods. We believe that our portfolio of intellectual property, which includes approximately 141 patents issued in the United States and more than 300 other patents issued worldwide, protects our product candidates and technologies. For additional information on us, please visit our website at www.immunomedics.com. The information on our website does not, however, form a part of this press release.
SOURCE: Immunomedics, Inc.
Post Views: 43
Immunomedics announced results from 3 preclinical studies aimed at understanding the mechanism of action of its proprietary humanized anti-CD74 antibody, milatuzumab, which is currently in clinical development for multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL)
NEW ORLEANS, LA, USA | December 7, 2009 | Immunomedics, Inc. (Nasdaq:IMMU – News), a biopharmaceutical company focused on developing monoclonal antibodies to treat cancer and other serious diseases, today at the 51st annual meeting of the American Society of Hematology announced results from 3 preclinical studies aimed at understanding the mechanism of action of its proprietary humanized anti-CD74 antibody, milatuzumab, which is currently in clinical development for multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
The first study was on CLL, a progressive disease for which most patients require treatment. A team of researchers at the Ohio State University, Columbus, OH, led by Dr. John Byrd, demonstrated expression of CD74 on the surface of CLL cells, but no expression was found on T cells. Milatuzumab-induced cell death occurred very rapidly, with 57% cell survival at 4 hours and only 30% at 24 hours, which was superior to that observed with rituximab.
The mode of cell death induced by milatuzumab was found to be mediated directly through interaction with CD74 and its ensuing effects on signal transduction. Milatuzumab, when crosslinked, promotes the maintenance of CD74 on the cell surface and thereby prevents receptor internalization and subsequent signaling. Retention of the CD74 receptor on the surface of B cells can also be induced, without the presence of a crosslinking antibody, the investigators found, by incorporating milatuzumab into liposomes.
The subject of the second study was mantle cell lymphoma (MCL), an incurable B-cell malignancy with limited therapeutic options. Despite the success of rituximab in treating B-cell lymphoma, its use as a single agent or in combination with chemotherapy in MCL has demonstrated modest activity. Since rituximab and milatuzumab target distinct antigens lacking known association, Dr. Byrd and his team at the Ohio State University, explored a combination strategy with these antibodies in MCL cell lines, patient samples, and in a preclinical model.
Primary tumor cells from MCL patients and 6 different MCL cell lines with variable levels of CD74 expression were used in this study. The combination of milatuzumab and rituximab was able to induce enhanced cell death in all MCL cell lines and MCL primary cells, regardless of antigen density. Moreover, milatuzumab-induced MCL cell death was found to be dependent on actin polymerization and inhibition of NF-kB, a protein complex that controls the transcription of DNA.
The in-vivo activity of rituximab and milatuzumab was examined in a preclinical model of human MCL in mice, with survival as the primary end-point. The mean survival for the combination-treated group was 44.5 days, compared to 28 days for the group of mice treated with trastuzumab, a non-CD74 binding antibody, 33.5 days and 38 days for the milatuzumab-treated and rituximab-treated mice, respectively. Thus, the combination treatment prolonged survival providing justification for further evaluation of milatuzumab and rituximab in combination in MCL, according to the authors.
The third study, presented by Dr. Xiaochuan Chen of the Garden State Cancer Center, Belleville, NJ, assessed the binding profiles and functional effects of milatuzumab on human antigen-presenting cells (APC). Because CD74 is expressed in normal B cells, monocytes, macrophages, Langerhans cells, follicular and blood dendritic cells, the goal of this study was to evaluate if milatuzumab is toxic to or affects the function of these immune cells. In addition, binding and cytotoxicity on a panel of leukemia/lymphoma cell lines and CLL patient cells were tested to demonstrate the range of malignancies that can be treated with this antibody.
In correlation with the levels of CD74 expression, milatuzumab bound efficiently to different subsets of blood dendritic cells (DC), B lymphocytes, monocytes, and immature DCs derived from human monocytes in vitro, but not LPS-matured DCs. For malignant B cells, milatuzumab bound to the surface of 2/3 acute myeloid leukemia (AML), 2/2 MCL, 4/4 acute lymphoblastic leukemia (ALL), 1/1 hairy cell leukemia, 2/2 CLL, 7/7 NHL, and 5/6 MM cell lines, as well as cells of 4/6 CLL patient specimens.
Following incubation with milatuzumab, significant cytotoxicity was observed in 2/2 MCL, 2/2 CLL, 3/4 ALL, 1/1 hairy cell, 2/2 NHL, and 2/2 MM cell lines, and 3/4 CD74-positive CLL patient cells, but not in the AML cell lines. In contrast, milatuzumab had minimal effects on the viability of DCs or B cells that normally express CD74. Moreover, milatuzumab treatment did not alter DC maturation and DC-mediated T-cell functions, nor did it influence antigen presentation or cross-presentation.
We believe these results demonstrate that milatuzumab is a highly specific therapeutic antibody against B-cell malignancies with potentially minimal side effects. It also suggests that milatuzumab may be a promising novel delivery vehicle for in-vivo targeted vaccinations, given its efficient binding, but lack of cytotoxicity and functional disruption on CD74-expressing normal APCs.
These studies were supported in part by grants from the National Institutes of Health.
About Immunomedics
Immunomedics is a New Jersey-based biopharmaceutical company primarily focused on the development of monoclonal, antibody-based products for the targeted treatment of cancer, autoimmune and other serious diseases. We have developed a number of advanced proprietary technologies that allow us to create humanized antibodies that can be used either alone in unlabeled or "naked" form, or conjugated with radioactive isotopes, chemotherapeutics or toxins, in each case to create highly targeted agents. Using these technologies, we have built a pipeline of therapeutic product candidates that utilize several different mechanisms of action. We also have a majority ownership in IBC Pharmaceuticals, Inc., which is developing a novel Dock-and-Lock (DNL) methodology with us for making fusion proteins and multifunctional antibodies, and a new method of delivering imaging and therapeutic agents selectively to disease, especially different solid cancers (colorectal, lung, pancreas, etc.), by proprietary, antibody-based, pretargeting methods. We believe that our portfolio of intellectual property, which includes approximately 141 patents issued in the United States and more than 300 other patents issued worldwide, protects our product candidates and technologies. For additional information on us, please visit our website at www.immunomedics.com. The information on our website does not, however, form a part of this press release.
SOURCE: Immunomedics, Inc.
Post Views: 43
