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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 -
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 -
Journal of Experimental & Clinical... Oct 2014Resistance to Fas-mediated apoptosis limits the efficacy of currently available chemotherapy regimens. We identified CD74, which is known to be overexpressed in...
BACKGROUND
Resistance to Fas-mediated apoptosis limits the efficacy of currently available chemotherapy regimens. We identified CD74, which is known to be overexpressed in hematological malignancies, as one of the factors interfering with Fas-mediated apoptosis.
METHODS
CD74 expression was suppressed in human B-lymphoma cell lines, BJAB and Raji, by either transduction with lentivirus particles or transfection with episomal vector, both encoding CD74-specific shRNAs or non-target shRNA. Effect of CD74 expression on Fas signaling was evaluated by comparing survival of mice hydrodynamically transfected with vector encoding full-length CD74 or empty vector. Sensitivity of cells with suppressed CD74 expression to FasL, edelfosine, doxorubicin, and a humanized CD74-specific antibody, milatuzumab, was evaluated by flow cytometry and compared to control cells. Fas signaling in response to FasL stimulation and the expression of Fas signaling components were evaluated by Western blot. Surface expression of Fas was detected by flow cytometry.
RESULTS
We determined that cells with suppressed CD74 are more sensitive to FasL-induced apoptosis and Fas signaling-dependent chemotherapies, edelfosine and doxorubicin, than control CD74-expressing cells. On the other hand, expression of full-length CD74 in livers protected the mice from a lethal challenge with agonistic anti-Fas antibody Jo2. A detailed analysis of Fas signaling in cells lacking CD74 and control cells revealed increased cleavage/activation of pro-caspase-8 and corresponding enhancement of caspase-3 activation in the absence of CD74, suggesting that CD74 affects the immediate early steps in Fas signaling at the plasma membrane. Cells with suppressed CD74 expression showed increased staining of Fas receptor on their surface. Pre-treatment with milatuzumab sensitized BJAB cells to Fas-mediated apoptosis.
CONCLUSION
We anticipate that specific targeting of the CD74 on the cell surface will sensitize CD74-expressing cancer cells to Fas-mediated apoptosis, and thus will increase effectiveness of chemotherapy regimens for hematological malignancies.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Apoptosis; Dose-Response Relationship, Drug; Doxorubicin; Fas Ligand Protein; Histocompatibility Antigens Class II; Humans; Jurkat Cells; Liver; Lymphoma, B-Cell; Mice, Inbred C57BL; Phospholipid Ethers; RNA Interference; Signal Transduction; Transfection; fas Receptor
PubMed: 25304249
DOI: 10.1186/s13046-014-0080-y -
Leukemia & Lymphoma 2015Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical non-Hodgkin lymphoma (NHL) models. We conducted a phase 1 trial in previously...
Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical non-Hodgkin lymphoma (NHL) models. We conducted a phase 1 trial in previously treated B-cell malignancies. Dose escalation included four planned dose levels (1.5, 4, 6 and 8 mg/kg) with milatuzumab given twice weekly for 6 weeks. After dose level 1, the schedule was changed to daily (Monday-Friday) for 10 days. Twenty-two patients were treated. The most common possibly related toxicities were infusion reaction, anemia, lymphopenia, neutropenia and thrombocytopenia. Three patients experienced dose-limiting toxicity (neutropenia, neutropenia, rash) at dose levels 1, 2 and 4, respectively. Eight patients had stable disease, with no objective responses. The serum half-life of milatuzumab was ∼2 h. In seven patients, In-111 imaging showed no clear evidence of tumor targeting. The short half-life may reflect CD74 rapid internalization and presence on extratumoral tissues; this antigen sink must be overcome to capitalize on the promising preclinical activity of the drug.
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Biomarkers; Disease Progression; Drug Resistance, Neoplasm; Female; Histocompatibility Antigens Class II; Humans; Immunohistochemistry; Lymphoma, B-Cell; Male; Middle Aged; Neoplasm Staging; Recurrence; Retreatment; Tissue Distribution; Treatment Outcome
PubMed: 25754579
DOI: 10.3109/10428194.2015.1028052 -
Autophagy Mar 2012Inhibition of the autophagic pathway has recently revealed promising results in increasing pro-death activity of multiple cancer therapeutics. Here, we discuss our...
FTY720-induced blockage of autophagy enhances anticancer efficacy of milatuzumab in mantle cell lymphoma: is FTY720 the next autophagy-blocking agent in lymphoma treatment?
Inhibition of the autophagic pathway has recently revealed promising results in increasing pro-death activity of multiple cancer therapeutics. Here, we discuss our findings regarding the autophagy-blocking and anti-neoplastic effects of a synthetic sphingosine analog, FTY720, in mantle cell lymphoma (MCL). We also emphasize how FTY720 enhances the pro-death activity of the fully humanized monoclonal antibody milatuzumab by inhibiting the autophagy-lysosome dependent degradation of its therapeutic target, CD74. Our results provide justification for further evaluation of FTY720 and milatuzumab as a combination therapy for this aggressive B-cell malignancy.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Autophagy; Fingolimod Hydrochloride; Humans; Lymphoma, Mantle-Cell; Mice; Neoplasm Proteins; Phosphorylation; Propylene Glycols; Sphingosine; Treatment Outcome
PubMed: 22377620
DOI: 10.4161/auto.19050 -
Immunotherapy Feb 2018We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy...
We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy achieved overall response (OR) of 24%. Other monoclonal antibodies that have shown efficacy in combination therapy include siltuximab (OR: 66%), indatuximab (OR: 78%), isatuximab (OR: 64.5%), pembrolizumab (OR: 60%), bevacizumab (OR: 70%), dacetuzumab (OR: 39%) and lorvotuzumab (OR: 56.4%). No OR was observed with monotherapy using BI-505, siltuximab, bevacizumab, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab, lucatumumab, IPH2101, lorvotuzumab, BT062 and nivolumab. We included seven clinical trials on chimeric antigen receptor (CAR) T cells. CAR T-cell targets include BCMA, CD19, KLC and CD138. A recent experience of CAR T-cell (B-cell maturation antigen) therapy in advanced MM has shown global response of 100%. The future of monoclonal antibodies and adoptive T cells for MM treatment seems promising.
Topics: Humans; Immunotherapy; Multiple Myeloma
PubMed: 29421983
DOI: 10.2217/imt-2017-0136 -
British Journal of Haematology Nov 2013CD74, expressed in multiple myeloma (MM), was evaluated as a target for immunotherapy with milatuzumab (a humanized anti-CD74 antibody). In a multicentre dose escalation...
CD74, expressed in multiple myeloma (MM), was evaluated as a target for immunotherapy with milatuzumab (a humanized anti-CD74 antibody). In a multicentre dose escalation study, 25 patients with advanced MM received milatuzumab doses of 1.5 (N = 8), 4.0 (N = 9), 8.0 (N = 4) or 16.0 mg/kg (N = 4) administered twice weekly x 4. They had a median of 5 prior treatments (17 post ≥ 1 stem cell transplantation) and were refractory (N = 7) or relapsed (N = 18) with generally short-lived responses to last treatment (median 4.0 months). After increasing prophylactic medications and slowing administration, infusions were well tolerated (National Cancer Institute-Common Terminology Criteria v3 toxicity Grades 1-2) with no dose-limiting toxicity at higher doses. Only one patient developed borderline positive human anti-milatuzumab antibody titres of uncertain clinical significance. Although milatuzumab was rapidly cleared from circulation with little serum accumulation and low trough levels, B-cell levels were moderately decreased with treatment (median decrease, 34%). There were no objective responses by European Group for Blood and Marrow Transplantation criteria, but 5 of 19 patients (26%) who completed treatment in this heavily pretreated and generally refractory group had stable disease for ≥ 3 months post-treatment (one continuing for 17 months). Disease stabilization and evidence of pharmacodynamic activity support further development for use in combination with other agents or as a drug conjugate.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Dose-Response Relationship, Drug; Female; Histocompatibility Antigens Class II; Humans; Male; Middle Aged; Multiple Myeloma; Recurrence
PubMed: 24112026
DOI: 10.1111/bjh.12565 -
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 -
Experimental Hematology Sep 2015Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent...
Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent cytotoxicity in MCL cell lines and primary cells. OSU-2S increased the surface expression of CD74, a therapeutic antibody target in MCL cells. OSU-2S, in combination with anti-CD74 antibody milatuzumab, enhanced cytotoxicity in MCL. Moreover, MCL tumor antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeted immunonanoparticle-carrying OSU-2S (2A2-OSU-2S-ILP)-mediated selective cytotoxicity of MCL in vitro, as well as activity in a xenografted mouse model of MCL in vivo. The newly developed OSU-2S delivery using ROR1-directed immunonanoparticles provide selective targeting of OSU-2S to MCL and other ROR1(+) malignancies, sparing normal B cells.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antigens, Neoplasm; Cytotoxins; Drug Delivery Systems; Fingolimod Hydrochloride; Histocompatibility Antigens Class II; Humans; Lymphoma, Mantle-Cell; Mice; Mice, Inbred NOD; Propylene Glycols; Receptor Tyrosine Kinase-like Orphan Receptors; Sphingosine; Xenograft Model Antitumor Assays
PubMed: 25937048
DOI: 10.1016/j.exphem.2015.04.008 -
British Journal of Haematology Jul 2018
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents, Immunological; Female; Frail Elderly; Histocompatibility Antigens Class II; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Patient-Centered Care; Quality of Life
PubMed: 28466956
DOI: 10.1111/bjh.14726