In vitro and in vivo characterization of a novel antibody-like single-chain TCR human IgG1 fusion protein.
We have constructed a protein composed of a soluble single-chain TCR genetically linked to the constant domain of an IgG1 H chain. The Ag recognition portion of the protein binds to an unmutated peptide derived from human p53 (aa 264-272) presented in the context of HLA-A2.1, whereas the IgG1 H chain provides effector functions. The protein is capable of forming dimers, specifically staining tumor cells and promoting target and effector cell conjugation. The protein also has potent antitumor effects in an in vivo tumor model and can mediate cell killing by Ab-dependent cellular cytotoxicity. Therefore, single-chain TCRs linked to IgG1 H chains behave like Abs but possess the ability to recognize Ags derived from intracellular targets. These fusion proteins represent a novel group of immunotherapeutics that have the potential to expand the range of tumors available for targeted therapies beyond those currently addressed by the conventional Ab-based approach.
Mosquera
Luis A
LA
Altor BioScience Corporation, Miramar, FL 33025, USA.
Card
Kimberlyn F
KF
Price-Schiavi
Shari A
SA
Belmont
Heather J
HJ
Liu
Bai
B
Builes
Janette
J
Zhu
Xiaoyun
X
Chavaillaz
Pierre-Andre
PA
Lee
Hyung-Il
HI
Jiao
Jin-an
JA
Francis
John L
JL
Amirkhosravi
Ali
A
Wong
Richard L
RL
Wong
Hing C
HC
D000912:Antibodies, Neoplasm / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D019281:Dimerization; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics* / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D009369:Neoplasms / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000276:immunology
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53