Structural design of disialoganglioside GD2 and CD3-bispecific antibodies to redirect T cells for tumor therapy Journal Article


Authors: Cheng, M.; Ahmed, M.; Xu, H.; Cheung, N. K. V.
Article Title: Structural design of disialoganglioside GD2 and CD3-bispecific antibodies to redirect T cells for tumor therapy
Abstract: Antibody-based immunotherapy has proven efficacy for patients with high-risk neuroblastoma. However, despite being the most efficient tumoricidal effectors, T cells are underutilized because they lack Fc receptors. Using a monovalent single-chain fragment (ScFv) platform, we engineered tandem scFv bispecific antibodies (BsAbs) that specifically target disialoganglioside (GD2) on tumor cells and CD3 on T cells. Structural variants of BsAbs were constructed and ranked based on binding to GD2, and on competency in inducing T-cell-mediated tumor cytotoxicity. In vitro thermal stability and binding measurements were used to characterize each of the constructs, and in silico molecular modeling was used to show how the orientation of the variable region heavy (VH) and light (VL) chains of the anti-GD2 ScFv could alter the conformations of key residues responsible for high affinity binding. We showed that the VH-VL orientation, the (GGGGS)(3) linker, disulfide bond stabilization of scFv, when combined with an affinity matured mutation provided the most efficient BsAb to direct T cells to lyse GD2-positive tumor cells. In vivo, the optimized BsAb could efficiently inhibit melanoma and neuroblastoma xenograft growth. These findings provide preclinical validation of a structure-based method to assist in designing BsAb for T-cell-mediated therapy.
Keywords: cytotoxicity; immunotherapy; neuroblastoma; metastatic melanoma; acute lymphoblastic-leukemia; antitumor-activity; structure; disialoganglioside; construct; blinatumomab; anti-gd2 antibody; engaging antibody; bispecificity
Journal Title: International Journal of Cancer
Volume: 136
Issue: 2
ISSN: 0020-7136
Publisher: John Wiley & Sons  
Date Published: 2015-01-15
Start Page: 476
End Page: 486
Language: English
ACCESSION: WOS:000344596600025
DOI: 10.1002/ijc.29007
PROVIDER: wos
PUBMED: 24895182
PMCID: PMC4517675
Notes: Article -- Source: Wos
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MSK Authors
  1. Nai-Kong Cheung
    447 Cheung
  2. Mahiuddin Ahmed
    12 Ahmed
  3. Ming Cheng
    6 Cheng
  4. Hong Xu
    23 Xu