title: Synthesis and evaluation of the aldolase antibody-derived chemical-antibodies targeting α5β1 integrin.
abstract: Integrin α5β1 is an important therapeutic target that can be inhibited using an aldolase antibody (Ab)-derived chemical-Ab (chem-Ab) for the treatment of multiple human diseases, including cancers. A fairly optimized anti-integrin α5β1 chem-Ab 38C2-4e was obtained using an in situ convergent chemical programming (CP) approach, which minimized the time and effort needed to develop a chem-Ab. Multiple Ab-programming agents (PAs) 4a-e could be prepared rapidly using the Cu-catalyzed alkyne-azide coupling (Cu-AAC) reaction of an α5β1 inhibitor 2 with multiple linkers 3a-e, either before or after conjugating the linkers into Ab 38C2 binding sites. In these two-steps processes, the products after step 1 can be used in the next step without performing an extensive purification or analysis of the Ab-PAs or Ab-linker conjugates affording chem-Abs 38C2-(4a-e). Flow cytometry assay was used to determine the binding of the chem-Abs to U87 human glioblastoma cells expressing α5β1 integrin and identify 38C2-3e as the strongest binder. Further studies revealed that 38C2-3e strongly inhibited proliferation of U87 cells and tube formation of HUVEC in the matrigel assay, as well as tumor growth and metastasis of 4T1 cells in vivo.
authors.affiliation: Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Rajib K
authors.initials: RK
authors.lastname: Goswami
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Sinha
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D005634:Fructose-Bisphosphate Aldolase / Q000737:chemistry*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D039081:Integrin alpha5beta1; C109536:antibody aldolase; D005634:Fructose-Bisphosphate Aldolase