Development of α‐Gal–Antibody Conjugates to Increase Immune Response by Recruiting Natural Antibodies

Abstract

Cancer treatment with antibodies (Abs) is one of the most successful therapeutic strategies for obtaining high selectivity.I nt his study, a-gal-Ab conjugates were developed that dramatically increased cellular cytotoxicity by recruiting natural Abs through the interaction between a-gal and anti-gal Abs.The potency of the a-gal-Ab conjugates depended on the amount of a-gal conjugated to the antibody:t he larger the amount of a-gal introduced, the higher the level of cytotoxicity observed. The conjugation of antibodies with an a-gal dendrimer allowed the introduction of large amounts of agal to the Ab,w ithout loss of affinity for the target cell. The method described here will enable the re-development of Abs to improve their potency. Figure 1. Chemical structure of the a-gal epitope.

Synthesis of ABO blood group antigens and functional glycan display on the cell surface

“…Considering the successful staining with the fluoresceinlabeled anti-mouse IgG antibody, these results showed that B antigen loaded on anti-CD20 antibody was not recognized by the IgM antibody. In our previous report using -gal as a glycan antigen, we demonstrated -gal conjugated to anti-CD20 antibody in the same manner described in the current study was recognized by antibodies against -gal, 43 suggesting that accessibility of the glycan antigen on anti-CD20 antibody does not the issue. The difference in recognition of B antigen and -gal might be attributed to the binding affinity of the corresponding antibodies as antibodies against -gal contain a certain amount of IgG antibodies, which exhibit high affinity.…”

Structural influence of antibody recruiting glycodendrimers (ARGs) on antitumoral cytotoxicity

“…For this purpose, we followed the synthetic route described previously with lectins (Scheme 1), 12 which consists in the functionalization of the tetravalent azido cyclopeptide 1 and dendron 2 with propargylated cRGD and α-L-Rha by coppercatalysed azide-alkyne cycloaddition (CuAAC). The free lysine of the resulting compounds 3-5 was next conjugated by amide coupling with an activated ester of linker bearing either an azide (6-7), an alkyne (8-10) or a PEGylated azide (11). Finally, five different ARGs varying in the valency and the orientation of Rha (16CC, 16CD, 16DC, 16DD and 4C) and two structures having PEGylated spacer between ABM and TBM (4C-P and 16CC-P) were synthesized (Scheme 3).…”

“…Following the Ab-drug conjugate concept, α-Gal was alternatively conjugated to tumor-specific Abs to take advantage of the natural abundance of anti-α-Gal Abs in humans. 11 The introduction of α-Gal either as a single ligand or as a dendrimeric structure was shown to significantly increase the cellular cytotoxicity in the presence of human serum and after addition of rabbit complement.…”

Functional glycomics: Application to medical science and hepatology

“…For example, introduction of α1-3 galactosyltransferase gene to Muc-1 enhanced immunogenicity, leading to hyper rejection of muc-1-bearing tumors. 60 Thus, chemical synthesis of α1-3 gal-epitope can enhance cell toxicity, 66 offering a novel strategy for cancer immunotherapy.…”