Breaking the one antibody-one target axiom.
Studies at the interface of chemistry and biology have allowed us to develop an immunotherapeutic approach called chemically programmed antibodies (cpAbs), which combines the merits of traditional small-molecule drug design with immunotherapy. In this approach, a catalytic antibody catalyzes the covalent conjugation of a small molecule or peptide to the active site of the antibody, effectively recruiting the binding specificity of the conjugated molecule to the antibody. In essence, this technology provides the tools for breaking the "one antibody-one target axiom" of immunochemistry. Our studies in this area have focused on using the chemistry of the well studied aldolase catalytic antibodies of which mAb 38C2 is a member. Previously, we explored reversible assembly of cpAbs available through diketone chemistry. In this article, we explore a unique proadapter assembly strategy wherein an antibody 38C2-catalyzed transformation unveils a reactive tag that then reacts to form a stable covalent bond with the antibody. An integrin alpha(v)beta 3 antagonist was synthesized with the designed proadapter and studied using human breast cancer cell lines MDA-MB-231 and MDA-MB-435. We demonstrate that this approach allows for (i) the effective assembly of cpAbs in vitro and in vivo, (ii) selective retargeting of 38C2 to integrin alpha(v)beta 3 expressing breast cancer cell lines, (iii) intracellular delivery of cpAbs into cells, (iv) dramatically increased circulatory half-life, and (v) substantial enhancement of the therapeutic effect over the peptidomimetic itself in animal models of breast cancer metastasis. We believe that this technology possesses potential for the treatment and diagnosis of disease.
Guo
Fang
F
The Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Das
Sanjib
S
Mueller
Barbara M
BM
Barbas
Carlos F
CF
Lerner
Richard A
RA
Sinha
Subhash C
SC
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007158:Immunologic Techniques; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000276:immunology; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure
D000906:Antibodies; D000941:Antigens; D039302:Integrin alphaVbeta3