Enhanced antiangiogenic therapy with antibody-collagen XVIII NC1 domain fusion proteins engineered to exploit matrix remodeling events.
Antiangiogenic therapy is nowadays one of the most active fields in cancer research. The first strategies, aimed at inhibiting tumor vascularization, included upregulation of endogenous inhibitors and blocking of the signals delivered by angiogenic factors. But interaction between endothelial cells and their surrounding extracellular matrix also plays a critical role in the modulation of the angiogenic process. This study introduces a new concept to enhance the efficacy of antibody-based antiangiogenic cancer therapy strategies, taking advantage of a key molecular event occurring in the tumor context: the proteolysis of collagen XVIII, which releases the endogenous angiogenesis inhibitor endostatin. By fusing the collagen XVIII NC1 domain to an antiangiogenic single-chain antibody, a multispecific agent was generated, which was efficiently processed by tumor-associated proteinases to produce monomeric endostatin and fully functional trimeric antibody fragments. It was demonstrated that the combined production in the tumor area of complementary antiangiogenic agents from a single molecular entity secreted by gene-modified cells resulted in enhanced antitumor effects. These results indicate that tailoring recombinant antibodies with extracellular matrix-derived scaffolds is an effective approach to convert tumor progression associated processes into molecular clues for improving antibody-based therapies.
Department of Immunology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
Víctor J
VJ
Sánchez-Arévalo Lobo
Angel M
AM
Cuesta
Laura
L
Sanz
Marta
M
Compte
Pascal
P
García
Jesús
J
Prieto
Francisco J
FJ
Blanco
Luis
L
Alvarez-Vallina
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002850:Chromatography, Gel; D043170:Collagen Type XVIII / Q000276:immunology / Q000378:metabolism*; D043169:Endostatins / Q000096:biosynthesis / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000494:pharmacology*; D014162:Transfection
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D000970:Antineoplastic Agents; D043170:Collagen Type XVIII; D043169:Endostatins; D011993:Recombinant Fusion Proteins