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1.
Cancer Cell ; 27(4): 473-88, 2015 Apr 13.
Article in English | MEDLINE | ID: mdl-25873171

ABSTRACT

Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antibodies, Monoclonal/therapeutic use , Receptors, IgG/antagonists & inhibitors , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Murine-Derived/metabolism , Antibodies, Monoclonal, Murine-Derived/pharmacology , Drug Synergism , Humans , Mice , Neoplasms/drug therapy , Neoplasms/immunology , Receptors, IgG/physiology , Rituximab
2.
Clin Cancer Res ; 21(12): 2730-6, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-25712687

ABSTRACT

PURPOSE: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients. EXPERIMENTAL DESIGN: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses. RESULTS: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505's half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months. CONCLUSIONS: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206).


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Drug Monitoring , Female , Humans , Male , Middle Aged , Multiple Myeloma/diagnosis , Recurrence , Treatment Outcome
3.
Cancer Cell ; 23(4): 502-15, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-23597564

ABSTRACT

We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.


Subject(s)
Antibodies, Monoclonal/pharmacology , B-Lymphocytes/immunology , Intercellular Adhesion Molecule-1/immunology , Macrophages/immunology , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Adult , Aged , Aged, 80 and over , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/isolation & purification , B-Lymphocytes/metabolism , Cell Line, Tumor , Epitopes/biosynthesis , Epitopes/immunology , Female , Humans , Macrophages/metabolism , Male , Mice , Mice, SCID , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Peptide Library , Receptors, IgG/immunology , Xenograft Model Antitumor Assays
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