Therapeutic Antibodies to Ganglioside GD2 Evolved from Highly Selective Germline Antibodies

Publication date: 15 August 2017
Source:Cell Reports, Volume 20, Issue 7
Author(s): Eric Sterner, Megan L. Peach, Marc C. Nicklaus, Jeffrey C. Gildersleeve
Antibodies play a crucial role in host defense and are indispensable research tools, diagnostics, and therapeutics. Antibody generation involves binding of genomically encoded germline antibodies followed by somatic hypermutation and in vivo selection to obtain antibodies with high affinity and selectivity. Understanding this process is critical for developing monoclonal antibodies, designing effective vaccines, and understanding autoantibody formation. Prior studies have found that antibodies to haptens, peptides, and proteins evolve from polyspecific germline antibodies. The immunological evolution of antibodies to mammalian glycans has not been studied. Using glycan microarrays, protein microarrays, cell binding studies, and molecular modeling, we demonstrate that therapeutic antibodies to the tumor-associated ganglioside GD2 evolved from highly specific germline precursors. The results have important implications for developing vaccines and monoclonal antibodies that target carbohydrate antigens. In addition, they demonstrate an alternative pathway for antibody evolution within the immune system that is distinct from the polyspecific germline pathway.

Graphical abstract

Teaser

Sterner et al. demonstrate that germline antibodies to the mammalian glycan GD2 have unexpectedly high selectivity. No cross-reactivity was observed on a glycan microarray with 500 components or a human proteome array with 19,000 proteins. Molecular dynamics reveal pre-organized and relatively rigid binding pockets for the germline antibodies.


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