-
Expert Opinion on Investigational Drugs Jan 2010Milatuzumab is a new immunotherapeutic agent targeting CD74, a membrane protein preferentially expressed in hematopoietic cancers and some solid tumors. Broad expression... (Review)
Review
Milatuzumab is a new immunotherapeutic agent targeting CD74, a membrane protein preferentially expressed in hematopoietic cancers and some solid tumors. Broad expression and fast internalization makes CD74 an ideal target for cancer therapy. We reviewed published articles about CD74 and milatuzumab. We present a comprehensive review of CD74 functions and provide explanation of milatuzumab antitumor effects. This review describes CD74 protein biology with the emphasis on the role of CD74 in tumor survival and its new role in regulation of the Fas death receptor. The development of CD74 targeting therapies to induce tumor regression and cancer cell apoptosis is described and results of clinical trials are discussed. Milatuzumab shows selective binding and rapid internalization into CD74-positive cancer cells. Milatuzumab with and without conjugated toxins synergizes with other chemotherapeutic agents and elicits significant antitumor effects in mice. In a Phase I trial, milatuzumab showed no severe adverse effects in patients with relapsed/refractory multiple myeloma and it stabilized the disease in some patients for up to 12 weeks. Ongoing trials testing different treatment schedules of milatuzumab in chronic lymphocytic leukemia, non-Hodgkin's lymphoma and multiple myeloma indicate that milatuzumab shows no severe adverse effects in humans.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Histocompatibility Antigens Class II; Humans; Immunotherapy; Neoplasms
PubMed: 19968579
DOI: 10.1517/13543780903463854 -
Expert Opinion on Investigational Drugs Jan 2009Non-Hodgkin's lymphoma and multiple myeloma are often incurable and respond to a limited set of treatment options. The selective expression of CD74, the invariant chain... (Review)
Review
BACKGROUND
Non-Hodgkin's lymphoma and multiple myeloma are often incurable and respond to a limited set of treatment options. The selective expression of CD74, the invariant chain of the MHC class II molecule, in these malignancies provides an attractive target for antibody-based therapy.
OBJECTIVE
This review evaluates the preclinical data for milatuzumab, a humanized antibody targeting CD74, as a treatment for non-Hodgkin's lymphomas and multiple myeloma.
METHODS
A review of the literature was carried out using PubMed. Current Phase I protocols using milatuzumab are summarized.
RESULTS/CONCLUSION
Milatuzumab is cytotoxic to lymphoma and multiple myeloma cell lines and mouse-human xenografts. The efficacy dramatically increases when milatuzumab is attached to a toxin or a radioactive agent. Phase I trials of milatuzumab are now underway in human subjects with lymphoma and multiple myeloma.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Clinical Trials as Topic; Drug Evaluation, Preclinical; Histocompatibility Antigens Class II; Humans; Immunotherapy; Lymphoma
PubMed: 19053886
DOI: 10.1517/13543780802636162 -
Molecular Cancer Therapeutics Jun 2013CD74 is an attractive target for antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematologic...
CD74 is an attractive target for antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematologic tumors but is expressed also in solid cancers. Therefore, ADCs of the humanized anti-CD74 antibody, milatuzumab, were examined for the therapy of CD74-expressing solid tumors. Milatuzumab-doxorubicin and two milatuzumab-SN-38 conjugates with cleavable linkers, differing in their stability in serum and how they release SN-38 in the lysosome, were prepared. CD74 expression was determined by flow cytometry and immunohistology. In vitro cytotoxicity and in vivo therapeutic studies were conducted in the human cancer cell lines A-375 (melanoma), HuH-7 and Hep-G2 (hepatoma), Capan-1 (pancreatic), NCI-N87 (gastric), and Raji Burkitt lymphoma. The milatuzumab-SN-38 ADC was compared with SN-38 ADCs prepared with anti-Trop-2 and anti-CEACAM6 antibodies in xenografts expressing their target antigens. Milatuzumab-doxorubicin was most effective in the lymphoma model, whereas in A-375 and Capan-1 solid tumors, only milatuzumab-SN-38 showed a therapeutic benefit. Despite much lower surface expression of CD74 than Trop-2 or CEACAM6, milatuzumab-SN-38 had similar efficacy in Capan-1 as anti-Trop-2-SN-38, but in NCI-N87, anti-CEACAM6 and anti-Trop-2 conjugates were superior. Studies in two hepatoma lines at a single dose level showed significant benefit over saline controls but not against an irrelevant immunoglobulin G conjugate. CD74 is a suitable target for ADCs in some solid tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression and with SN-38 conjugates providing the best therapeutic responses; SN-38 conjugates were preferable in solid cancers, whereas doxorubicin ADC was better in lymphoma tested.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antigens, Neoplasm; Camptothecin; Cell Adhesion Molecules; Doxorubicin; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Histocompatibility Antigens Class II; Humans; Irinotecan; Neoplasms; Xenograft Model Antitumor Assays
PubMed: 23427296
DOI: 10.1158/1535-7163.MCT-12-1170 -
Annals of the Rheumatic Diseases Jul 2021
Randomized Controlled Trial
Topics: Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Double-Blind Method; Histocompatibility Antigens Class II; Humans; Intramolecular Oxidoreductases; Lupus Erythematosus, Systemic; Macrophage Migration-Inhibitory Factors
PubMed: 33619162
DOI: 10.1136/annrheumdis-2020-219803 -
Blood Oct 2010Chronic lymphocytic leukemia (CLL) is an incurable progressive disease for which new therapies are required. Therapy with monoclonal antibodies (mAbs) has improved the...
Chronic lymphocytic leukemia (CLL) is an incurable progressive disease for which new therapies are required. Therapy with monoclonal antibodies (mAbs) has improved the outcome of patients with CLL, making further investigation of novel antibodies directed against alternative and specific targets on B cells an important area of translational research. We now describe functional properties of an antagonistic humanized mAb to CD74, milatuzumab, showing that milatuzumab combined with a crosslinking antibody induces cytotoxicity in vitro in CLL cells in a caspase- and stromal-independent manner associated with aggregation of CD74 on the cell surface. Furthermore, incorporation of milatuzumab into an immunoliposome induces even more of a cytotoxic response than in vitro crosslinking, representing a novel therapeutic formulation for this mAb. Based on these data, future development of the milatuzumab-immunoliposome formulation as a therapeutic agent for CLL is warranted.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; B-Lymphocytes; Cell Death; Histocompatibility Antigens Class II; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Liposomes
PubMed: 20574049
DOI: 10.1182/blood-2009-11-253203 -
Clinical Cancer Research : An Official... Jan 2013Corticosteroids are widely used for the treatment of B-cell malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic...
PURPOSE
Corticosteroids are widely used for the treatment of B-cell malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia; however, this class of drug is associated with undesirable off-target effects. Herein, we developed novel milatuzumab-conjugated liposomes as a targeted dexamethasone carrier for therapeutic delivery in CD74(+) B-cell malignancies and explored its effect against the disease.
EXPERIMENTAL DESIGN
The targeting efficiency of milatuzumab-targeted liposomes to CD74(+) cells was evaluated in vitro. The effect of CD74-targeted liposomal dexamethasone was compared with free dexamethasone in primary CLL cells and cell lines in vitro. The therapeutic efficacy of CD74-targeted liposomal dexamethasone was evaluated in a Raji-severe combined immunodeficient (SCID) xenograft model in vivo.
RESULTS
Milatuzumab-targeted liposomes promoted selective incorporation of carrier molecules into transformed CD74-positive B cells as compared with CD74-negative T-cells. The CD74-dexamethasone-targeted liposomes (CD74-IL-DEX) promoted and increased killing in CD74-positive tumor cells and primary CLL cells. Furthermore, the targeted drug liposomes showed enhanced therapeutic efficacy against a CD74-positive B-cell model as compared with free, or non-targeted, liposomal dexamethasone in SCID mice engrafted with Raji cells in vivo.
CONCLUSIONS
These studies provide evidence and support for a potential use of CD74-targeted liposomal dexamethasone as a new therapy for B-cell malignancies.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Cell Line, Tumor; Dexamethasone; Disease Models, Animal; Female; Histocompatibility Antigens Class II; Humans; Leukemia, B-Cell; Liposomes; Lymphoma, B-Cell; Mice; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 23209030
DOI: 10.1158/1078-0432.CCR-12-2046 -
Clinical Cancer Research : An Official... Apr 2009The humanized anti-CD74 monoclonal antibody, milatuzumab, is in clinical evaluation for the therapy of multiple myeloma (MM). The ability of milatuzumab to increase the...
PURPOSE
The humanized anti-CD74 monoclonal antibody, milatuzumab, is in clinical evaluation for the therapy of multiple myeloma (MM). The ability of milatuzumab to increase the efficacy of bortezomib, doxorubicin, and dexamethasone was examined in three human CD74+ MM cell lines, CAG, KMS11, KMS12-PE, and one CD74-MM cell line, OPM-2.
EXPERIMENTAL DESIGN
Activity of milatuzumab as a monotherapy and combined with the drugs was evaluated by studying in vitro cytotoxicity, signaling and apoptotic pathways, and in vivo therapeutic activity in severe combined immunodeficient (SCID) mouse models of MM.
RESULTS
Given as a monotherapy, cross-linked milatuzumab, but not milatuzumab alone, yielded significant antiproliferative effects in CD74+ cells. The combination of cross-linked milatuzumab with bortezomib, doxorubicin, or dexamethasone caused more growth inhibition than either cross-linked milatuzumab or drug alone, producing significant reductions in the IC(50) of the drugs when combined. Efficacy of combined treatments was accompanied by increased levels of apoptosis measured by increases of activated caspase-3 and hypodiploid DNA. Both milatuzumab and bortezomib affect the nuclear factor-kappaB pathway in CAG MM cells. In CAG- or KMS11-SCID xenograft models of disseminated MM, milatuzumab more than doubled median survival time, compared with up to a 33% increase in median survival with bortezomib but no significant benefit with doxorubicin. Moreover, combining milatuzumab and bortezomib increased survival significantly compared with either treatment alone.
CONCLUSIONS
The therapeutic efficacies of bortezomib, doxorubicin, and dexamethasone are enhanced in MM cell lines when given in combination with milatuzumab, suggesting testing these combinations clinically.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; Caspase 3; Cell Line, Tumor; DNA Fragmentation; Dexamethasone; Doxorubicin; Histocompatibility Antigens Class II; Humans; Mice; Mice, SCID; Multiple Myeloma; Pyrazines
PubMed: 19351768
DOI: 10.1158/1078-0432.CCR-08-1953 -
British Journal of Haematology Apr 2014
Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Humans; Lymphoma, Follicular; MAP Kinase Signaling System; Mice; NF-kappa B
PubMed: 24386925
DOI: 10.1111/bjh.12711 -
Blood Apr 2011Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal...
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.
Topics: Antibodies, Immobilized; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cytoskeleton; Drug Therapy, Combination; Flow Cytometry; Histocompatibility Antigens Class II; Humans; In Vitro Techniques; Lymphoma, Mantle-Cell; Membrane Potential, Mitochondrial; NF-kappa B; Reactive Oxygen Species; Rituximab
PubMed: 21228331
DOI: 10.1182/blood-2010-08-303354 -
British Journal of Haematology Jun 2015As a result of the anti-tumour activity observed in vitro and in vivo with combined anti-CD20 and anti-CD74 antibodies, we initiated a phase I/II trial of veltuzumab and...
The combination of milatuzumab, a humanized anti-CD74 antibody, and veltuzumab, a humanized anti-CD20 antibody, demonstrates activity in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
As a result of the anti-tumour activity observed in vitro and in vivo with combined anti-CD20 and anti-CD74 antibodies, we initiated a phase I/II trial of veltuzumab and milatuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). Patients received an induction of veltuzumab 200 mg/m(2) weekly combined with escalating doses of milatuzumab at 8, 16 and 20 mg/kg weekly for 4 weeks. Patients without disease progression could receive an extended induction with treatment on weeks 12, 20, 28 and 36. A total of 35 patients enrolled on the study. Median age was 63 years, median number of prior therapies was 3, and 63% of patients were rituximab refractory. No dose-limiting toxicities were observed in the phase I study. Related grade 3-4 toxicities included lymphopenia, leucopenia, neutropenia, anaemia, infusion reactions, hyperglycaemia, fatigue and atrial tachycardia. Median weeks of therapy was 12 and 29% of patients completed all 36 weeks of therapy. The overall response rate was 24%, median duration of response was 12 months, and responses were observed at all dose levels and in 50% of patients refractory to rituximab. Combination therapy with veltuzumab and milatuzumab demonstrated activity in a population of heavily pre-treated patients with relapsed or refractory indolent NHL.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Grading; Treatment Outcome
PubMed: 25847298
DOI: 10.1111/bjh.13354