title: Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model.
abstract: Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008) Clin. Cancer Res. 14: 7981-7986), although at widely varying rates and by different mechanisms (Dello Sbarba & Rovida (2002) Biol. Chem. 383: 69-83). Why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs are poorly understood questions at present. Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins. However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules. Here, we improved this model and applied it to both SS1P and another recombinant immunotoxin, LMB-2, which targets CD25. We show that the effect of antigen shedding is influenced by a number of factors including the number of antigen molecules on the cell surface and the endocytosis rate. The high shedding rate of mesothelin is beneficial for SS1P, for which the antigen is large in number and endocytosed rapidly. On the other hand, the slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly.
authors.affiliation: Department of Chemistry and Institute of Functional Materials, Pusan National University, Busan, Republic of Korea; Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Youngshang
authors.initials: Y
authors.lastname: Pak
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kreitman
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Byungkook
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005098:Exotoxins / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; C474515:SS1(dsFv)PE38