Endowing self-binding feature restores the activities of a loss-of-function chimerized anti-GM2 antibody.
Our previous studies have described a rare type of antibody that spontaneously binds to itself, or homodimerizes. This self-binding, or autophilic antibody provides stronger protection against bacterial infection than a non-self-binding antibody with identical specificity and affinity, due to an increase of polymeric avidity. Furthermore, we have shown that a peptide derived from the self-binding domain of the autophilic T15 antibody can be crosslinked to the Fc carbohydrate of monoclonal antibodies specific for the B-cell receptor of B-cell tumors. These peptide-crosslinked antibodies can exert self-binding properties, leading to an increase in binding efficiency to the target cells as well as an increase in potential to induce apoptosis. Herein, we report a novel finding that crosslinking of the autophilic T15 peptide rescues a loss-of-function chimerized (ch) anti-GM2 antibody. The parental antibody demonstrates in vivo anti-tumor activity against melanoma xenografts. The T15 peptide-conjugated antibody shows the ability to bind to itself, as well as an increased binding to its antigen, ganglioside GM2. Moreover, the peptide-conjugated antibody also demonstrates an increased ability to bind to two GM2-positive tumor cell lines and notably important, restores its ability to induce apoptosis in two types of tumor cells. These results provide strong support for the clinical potential of the autophilic technology.
Zhao
Yunfeng
Y
Innexus/Immpheron Laboratory, UK Coldstream Research Campus, 1501 Bull Lea Road, Suite 105, Lexington, KY 40511, USA.
Russ
Michael
M
Retter
Marc
M
Fanger
Gary
G
Morgan
Charles
C
Kohler
Heinz
H
Muller
Sybille
S
D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D002678:Chimera; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005678:G(M2) Ganglioside / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D009369:Neoplasms / Q000276:immunology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D005678:G(M2) Ganglioside