Tailored cancer immunotherapy using combinations of chemotherapy and a mixture of antibodies against EGF-receptor ligands.
Growth factors are implicated in several processes essential for cancer progression. Specifically, growth factors that bind to ErbB family receptors have been implicated in cell proliferation and in resistance of solid tumors to chemotherapy. We quantified ligand secretion by several human cancer cell lines, and generated mAbs against two ligands, namely TGF-alpha and heparin-binding EGF-like growth factor. These growth factors are frequently secreted by pancreatic tumor cell lines, including BxPC3 cells. The monoclonal antibodies were tested for their antigen specificity and ability to inhibit growth of BxPC3 cells in vitro. Combining the two antibodies resulted in enhanced inhibition of BxPC3 cell growth, both in vitro and in tumor-bearing animals. Hence, we combined the two antibodies with gemcitabine, an effective chemotherapeutic drug commonly used to treat pancreatic cancer patients. Because treatment with a combination of two monoclonal antibodies enhanced the ability of chemotherapy to inhibit BxPC3 tumors in mice, we propose a general cancer therapeutic strategy that entails profiling the repertoire of growth factors secreted by a tumor, and combining with chemotherapy several antibodies capable of blocking autocrine ligands.
Lindzen
Moshit
M
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Lavi
Sara
S
Leitner
Orith
O
Yarden
Yosef
Y
D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000918:Antibody Specificity / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007167:Immunotherapy; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000093542:Gemcitabine
D000906:Antibodies; D000911:Antibodies, Monoclonal; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D003841:Deoxycytidine; D066246:ErbB Receptors; D000093542:Gemcitabine