Thymoglobulin targets multiple plasma cell antigens and has in vitro and in vivo activity in multiple myeloma.
Multiple myeloma is characterized by the proliferation of clonal plasma cells that have a heterogeneous expression of various cell surface markers, precluding successful use of monoclonal antibodies for therapeutic targeting of the tumor cell. Thymoglobulin (rabbit-derived polyclonal anti-thymocyte globulin), by virtue of its method of preparation, contains antibodies against several B-cell and plasma cell antigens and offers an attractive option for immunotherapy of myeloma. Here, we demonstrate potent anti-myeloma activity of the rabbit anti-thymocyte globulin preparation Thymoglobulin in vitro and in vivo in an animal model of myeloma. Thymoglobulin was able to induce dose- and time-dependent apoptosis of several myeloma cell lines, including those resistant to conventional anti-myeloma agents. Importantly, the anti-myeloma activity was preserved even when myeloma cells were grown with different cytokines demonstrating the ability to overcome microenvironment-mediated resistance. Thymoglobulin induced apoptosis of freshly isolated primary myeloma cells from patients. Using a competitive flow cytometric analysis, we were able to identify the potential antigen targets for Thymoglobulin preparation. Finally, in a plasmacytoma mouse model of myeloma, Thymoglobulin delayed the tumor growth in a dose-dependent manner providing convincing evidence for continued evaluation of this agent in the clinic in patients with myeloma, either alone or in combination with other agents.
Timm
M M
MM
Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
Kimlinger
T K
TK
Haug
J L
JL
Kline
M P
MP
Greipp
P R
PR
Rajkumar
S V
SV
Kumar
S K
SK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D000961:Antilymphocyte Serum; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D066298:In Vitro Techniques; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D010950:Plasma Cells / Q000276:immunology*; D011817:Rabbits
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000961:Antilymphocyte Serum; D018906:Antineoplastic Agents, Alkylating; C512542:thymoglobulin; D008558:Melphalan