chFRP5-ZZ-PE38, a large IgG-toxin immunoconjugate outperforms the corresponding smaller FRP5(Fv)-ETA immunotoxin in eradicating ErbB2-expressing tumor xenografts.
As therapeutics, antibodies can be used "un-armed" or as immunoconjugates to direct cytotoxic moieties to tumor cells. Immunoconjugates are made by attaching chemotherapy drugs, radioisotopes or toxins to the antibody. Small recombinant antibody fragments fused to cytotoxic moieties, termed recombinant immunotoxins are also being developed as an additional approach for a targeted cancer therapy. Key parameters in determining the therapeutic potential of such targeted therapies are target specificity, affinity, stability and size. With regard to treating solid tumors, tumor penetration (which is inversely proportional to size) is currently regarded as the prime factor for efficacy, while parameters such as binding affinity and residence time in the body are thought to contribute to a lesser extent. When comparing recombinant immunotoxins and antibody-toxin immunoconjugates that target ErbB2/HER2, here we found that a bivalent antibody-toxin immunoconjugate (200 kDa) was superior to the corresponding recombinant monovalent immunotoxin (69 kDa) in killing ErbB2-expressing tumor cells in culture and as xenografts in nude mice, suggesting that higher avidity and longer residence time may outweigh tumor penetration. Our study suggests that the re-valuation of currently neglected, large IgG-effector molecule conjugates for anti-cancer therapy may be justified.
Mazor
Yariv
Y
Department of Molecular Microbiology and Biotechnology the George S. Wise Faculty of Life Sciences, Green Building, Room 202, Tel-Aviv University, Ramat Aviv 69978, Israel.
Noy
Roy
R
Wels
Winfried S
WS
Benhar
Itai
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000737:chemistry*; D000922:Immunotoxins / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; C525064:chFRP5-ZZ-PE38