Multiformat T-cell-engaging bispecific antibodies targeting human breast cancers.
Four different formats of bispecific antibodies (bsAbs) were generated that consist of anti-Her2 IgG or Fab site-specifically conjugated to anti-CD3 Fab using the genetically encoded noncanonical amino acid. These bsAbs varied in valency or in the presence or absence of an Fc domain. Different valencies did not significantly affect antitumor efficacy, whereas the presence of an Fc domain enhanced cytotoxic activity, but triggered antigen-independent T-cell activation. We show that the bsAbs can efficiently redirect T cells to kill all Her2 expressing cancer cells, including Her2 1+ cancers, both in vitro and in rodent xenograft models. This work increases our understanding of the structural features that affect bsAb activity, and underscores the potential of bsAbs as a promising therapeutic option for breast cancer patients with low or heterogeneous Her2 expression.
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Yu
Y
Cao
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Jun Y
JY
Axup
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Jennifer S Y
JS
Ma
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Rongsheng E
RE
Wang
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Seihyun
S
Choi
Department of Immunology and Microbial Science, The Scripps Research Institute (USA).
Virginie
V
Tardif
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Reyna K V
RK
Lim
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Holly M
HM
Pugh
Department of Immunology and Microbial Science, The Scripps Research Institute (USA).
Brian R
BR
Lawson
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Gus
G
Welzel
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Stephanie A
SA
Kazane
EuCode Technology, Ambrx, Inc. 10975 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Ying
Y
Sun
EuCode Technology, Ambrx, Inc. 10975 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Feng
F
Tian
EuCode Technology, Ambrx, Inc. 10975 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Shailaja
S
Srinagesh
EuCode Technology, Ambrx, Inc. 10975 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
Tsotne
T
Javahishvili
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA). Schultz@scripps.edu.|California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA). Schultz@scripps.edu.
Peter G
PG
Schultz
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA). chkim@calibr.org.
Chan Hyuk
CH
Kim
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D011961:Receptors, Fc / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D000068878:Trastuzumab / Q000737:chemistry / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D017252:CD3 Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc; D000068878:Trastuzumab; C508053:ERBB2 protein, human
T-cell activation; antibody drug conjugates; bispecific antibodies; breast cancers; noncanonical amino acids