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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 -
Journal of Nuclear Medicine : Official... Mar 2009We determined whether therapeutic responses using a bispecific antibody that pretargeted (90)Y-hapten-peptide radioimmunotherapy or a directly radiolabeled, humanized,... (Comparative Study)
Comparative Study
UNLABELLED
We determined whether therapeutic responses using a bispecific antibody that pretargeted (90)Y-hapten-peptide radioimmunotherapy or a directly radiolabeled, humanized, (90)Y-anti-CD20 IgG (veltuzumab) could be improved by combining these treatments with unlabeled humanized antibodies against CD22 (epratuzumab), CD74 (milatuzumab), or veltuzumab.
METHODS
Nude mice bearing established subcutaneous Ramos human Burkitt lymphoma were treated with antibodies alone or in combination with pretargeted radioimmunotherapy (PT-RAIT) or radioimmunotherapy, and tumor growth was monitored. Biodistribution studies examined the effect that predosing with unlabeled veltuzumab had on radioimmunotherapy and PT-RAIT targeting.
RESULTS
None of the unconjugated antibodies was effective against established and rapidly growing xenografts, but PT-RAIT, at approximately 30% of its maximum tolerated dose, and radioimmunotherapy alone, at its maximum tolerated dose, were able to arrest growth and even entirely ablate tumors in some animals. Only combinations with veltuzumab improved therapeutic responses, most significantly when a veltuzumab regimen (weekly, 1.0 mg followed by 3 x 0.5 mg) was initiated 1 wk after PT-RAIT or (90)Y-veltuzumab. Biodistribution data indicated that when unlabeled veltuzumab (1.0 or 0.25 mg) was administered in advance of the radiolabeled veltuzumab or bispecific antibody injection, tumor uptake was significantly reduced ((111)In-veltuzumab, 47% and 25%, respectively; (111)In-hapten-peptide, 74% and 49%, respectively). Despite an approximately 50% decrease in radioactivity uptake in the tumor, antitumor responses were not diminished significantly for (90)Y-veltuzumab, and in the case of PT-RAIT responses were improved. However, higher amounts of predosed veltuzumab reduced the effects of PT-RAIT.
CONCLUSION
These studies suggest that administering unlabeled anti-CD20 IgG therapy after the radioactivity dose provides the best efficacy and that the amount of unlabeled anti-CD20 IgG administered as a predose to anti-CD20-targeted radionuclide therapy should be minimized.
Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antigens, Differentiation, B-Lymphocyte; Burkitt Lymphoma; Drug Therapy, Combination; Histocompatibility Antigens Class II; Humans; Indium Radioisotopes; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Radioimmunotherapy; Radiopharmaceuticals; Sialic Acid Binding Ig-like Lectin 2; Transplantation, Heterologous; Yttrium Radioisotopes
PubMed: 19223402
DOI: 10.2967/jnumed.108.058602 -
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 -
Clinical Cancer Research : An Official... Sep 2007CD74 is an integral membrane protein that functions as a MHC class II chaperone. Moreover, it has recently been shown to have a role as an accessory-signaling molecule... (Review)
Review
CD74 is an integral membrane protein that functions as a MHC class II chaperone. Moreover, it has recently been shown to have a role as an accessory-signaling molecule and has been implicated in malignant B-cell proliferation and survival. These biological functions combined with expression of CD74 on malignant B cells and limited expression on normal tissues implicate CD74 as a potential therapeutic target. The anti-CD74 monoclonal antibody LL1 has been humanized (hLL1 milatuzumab or IMMU-115) and can provide the basis for novel therapeutic approaches to B-cell malignancies, particularly because this antibody shows rapid internalization into CD74+ malignant cells. This article reviews the preclinical evaluations of LL1, its humanized form, and isotope, drug, and toxin conjugates. These studies show that unconjugated hLL1 and conjugates of hLL1 constructs with radioisotopes, doxorubicin, and frog RNase have high antitumor activity in non-Hodgkin's lymphoma and multiple myeloma in vitro and in tumor xenograft models. Single-dose studies of hLL1 in monkeys showed no adverse effects but did decrease circulating B and T lymphocytes and natural killer cells. When evaluated in combination with rituximab, either equivalent or improved efficacy, compared with either antibody alone, was observed. CD74 is a new candidate target for the immunotherapy of neoplasms expressing this antigen, which can be exploited using either a naked antibody or conjugated to isotopes, drugs, or toxins.
Topics: Animals; Antibodies, Monoclonal; Antigens, Differentiation, B-Lymphocyte; Histocompatibility Antigens Class II; Humans; Immunotherapy; Lymphoma, B-Cell; Multiple Myeloma; Xenograft Model Antitumor Assays
PubMed: 17875789
DOI: 10.1158/1078-0432.CCR-07-1167