Chau Cheng, PhD, Director, Investor Relations & Grant Management; Immunomedics Inc., Morris Plains, N.J.
Immunomedics has developed a novel humanized antibody, milatuzumab, targeting CD74, a membrane protein.1 Also known as invariant chain, CD74 has been implicated in antigen processing—particularly by dendritic and other immune cells—and has been found to be a survival factor for rapidly proliferating malignant cells. CD74 is an attractive target for antibody therapy because it is preferentially expressed in hematopoietic cancers and certain solid tumors, and is rapidly internalized when bound.
More recent findings have determined that CD74 is a cellular receptor for the pro-inflammatory chemokine macrophage migration-inhibitory factor (MIF)2 and that binding of MIF to CD74 initiates a signaling cascade resulting in proliferation and survival.3 MIF is widely expressed by immune cells, particularly macrophages, and is known to play a role in autoimmune disease. These studies suggest that by blocking the function of CD74, milatuzumab could be useful in the management of autoimmune diseases either alone or in combination with other agents— including other B-cell antibodies.
Milatuzumab demonstrated antiproliferative effects on cancer cell lines derived from non-Hodgkin lymphoma (NHL), multiple myeloma, and chronic lymphocytic leukemia, as well as corresponding tumor xenograft models. As a monotherapy, the anti-CD74 antibody has been shown to be safe in Phase 1/2 trials in these cancer types with some evidence of clinical activity.4 Moreover, it is not an acute depleter of B cells, but shows a transient decrease of 25 to 50% of cells, thus permitting the patient to retain B-cell immune functions to infections.
A trial of 18 NHL patients who were previously treated with rituximab therapy showed that combination therapy with milatuzumab and the anti-CD20 antibody veltuzumab was active and well-tolerated.5 Overall, 14 patients had evidence of antitumor activity, with 4 patients (22%) having an objective response, including 2 complete responses. The patients who achieved a complete response include a patient with grade 1-2 follicular NHL who was rituximab-refractory and had undergone an allogeneic transplant; another patient with marginal zone lymphoma remained in remission after 13 months. Partial responses were seen in two patients with grade 3 follicular NHL refractory to rituximab. Stable disease ranging from 2.5 months to 12 months with a median duration of 5.25 months was observed in 10 patients.
Milatuzumab is the first anti-CD74 antibody to have entered into human testing and has received orphan drug designation from the U.S. Food and Drug Administration for the treatment of multiple myeloma and chronic lymphocytic leukemia.
References
1. Stein R, et al. CD74: a new candidate target for the immunotherapy of B-cell neoplasms. Clin Cancer Res. 2007; 13:5556s-5563s.
2. Leng L, et al. MIF signal transduction initiated by binding to CD74. J Exp Med. 2003; 197: 1467-76.
3. Starlets D, et al. Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival. Blood. 2006; 107:4807-16.
4. Kaufman JL, et al. Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma. J Clin Oncol. 2009; 27:15s (suppl; abstr 8593).
5. Christian B, et al. Results of 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 ASH Annual Meeting Abstract. 2011; 118: 3707.
More recent findings have determined that CD74 is a cellular receptor for the pro-inflammatory chemokine macrophage migration-inhibitory factor (MIF)2 and that binding of MIF to CD74 initiates a signaling cascade resulting in proliferation and survival.3 MIF is widely expressed by immune cells, particularly macrophages, and is known to play a role in autoimmune disease. These studies suggest that by blocking the function of CD74, milatuzumab could be useful in the management of autoimmune diseases either alone or in combination with other agents— including other B-cell antibodies.
Milatuzumab demonstrated antiproliferative effects on cancer cell lines derived from non-Hodgkin lymphoma (NHL), multiple myeloma, and chronic lymphocytic leukemia, as well as corresponding tumor xenograft models. As a monotherapy, the anti-CD74 antibody has been shown to be safe in Phase 1/2 trials in these cancer types with some evidence of clinical activity.4 Moreover, it is not an acute depleter of B cells, but shows a transient decrease of 25 to 50% of cells, thus permitting the patient to retain B-cell immune functions to infections.
A trial of 18 NHL patients who were previously treated with rituximab therapy showed that combination therapy with milatuzumab and the anti-CD20 antibody veltuzumab was active and well-tolerated.5 Overall, 14 patients had evidence of antitumor activity, with 4 patients (22%) having an objective response, including 2 complete responses. The patients who achieved a complete response include a patient with grade 1-2 follicular NHL who was rituximab-refractory and had undergone an allogeneic transplant; another patient with marginal zone lymphoma remained in remission after 13 months. Partial responses were seen in two patients with grade 3 follicular NHL refractory to rituximab. Stable disease ranging from 2.5 months to 12 months with a median duration of 5.25 months was observed in 10 patients.
Milatuzumab is the first anti-CD74 antibody to have entered into human testing and has received orphan drug designation from the U.S. Food and Drug Administration for the treatment of multiple myeloma and chronic lymphocytic leukemia.
References
1. Stein R, et al. CD74: a new candidate target for the immunotherapy of B-cell neoplasms. Clin Cancer Res. 2007; 13:5556s-5563s.
2. Leng L, et al. MIF signal transduction initiated by binding to CD74. J Exp Med. 2003; 197: 1467-76.
3. Starlets D, et al. Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival. Blood. 2006; 107:4807-16.
4. Kaufman JL, et al. Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma. J Clin Oncol. 2009; 27:15s (suppl; abstr 8593).
5. Christian B, et al. Results of 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 ASH Annual Meeting Abstract. 2011; 118: 3707.
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