title: Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation.
abstract: An obstacle in the utilization of catalytic Abs for selective prodrug activation in cancer therapy has been systemic tumor targeting. Here we report the generation of catalytic Abs that effectively target tumor cells with undiminished prodrug activation capability. Ab conjugates were prepared by covalent conjugation of an integrin alpha(v)beta(3)-targeting antagonist to catalytic Ab 38C2 through either sulfide groups of cysteine residues generated by reduction of the disulfide bridges in the hinge region or surface lysine residues not involved in the catalytic activity. Using flow cytometry, the Ab conjugates were shown to bind efficiently to integrin alpha(v)beta(3)-expressing human breast cancer cells. The Ab conjugates also retained the retro-aldol activity of their parental catalytic Ab 38C2, as measured by methodol and doxorubicin (dox) prodrug activation. Complementing these Ab conjugates, an evolved set of dox prodrugs was designed and synthesized. Dox prodrugs that showed higher stability and lower toxicity were evaluated both in the presence and absence of the integrin alpha(v)beta(3)-targeting 38C2 conjugates for cell-killing efficacy by using human breast cancer cells. Our study reveals that cell targeting and prodrug activation capabilities can be efficiently combined for selective chemotherapy with novel dox prodrugs.
authors: Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Sunny
authors: S
authors: Abraham
authors: Fang
authors: F
authors: Guo
authors: Lian-Sheng
authors: LS
authors: Li
authors: Christoph
authors: C
authors: Rader
authors: Cheng
authors: C
authors: Liu
authors: Carlos F
authors: CF
authors: Barbas
authors: Richard A
authors: RA
authors: Lerner
authors: Subhash C
authors: SC
authors: Sinha
mesh_terms: D000906:Antibodies / Q000737:chemistry*; D017151:Antibodies, Catalytic / Q000737:chemistry*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003545:Cysteine / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry; D015195:Drug Design; D005434:Flow Cytometry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008956:Models, Chemical; D011355:Prodrugs / Q000138:chemical synthesis*; D011485:Protein Binding; D013440:Sulfides / Q000737:chemistry
chemical_list: D000906:Antibodies; D017151:Antibodies, Catalytic; D039302:Integrin alphaVbeta3; D011355:Prodrugs; D013440:Sulfides; D004317:Doxorubicin; D003545:Cysteine