Antibody–peptide–MHC fusion conjugates target non-cognate T cells to kill tumour cells
| Autor: | Ted H. Hansen, Ruth R. French, Angela D. Hamblin, Ben C. King, Martin J. Glennie, Peter Johnson, Philip Savage, Leon Douglas |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research Immunoconjugates Ovalbumin Recombinant Fusion Proteins T-Lymphocytes medicine.medical_treatment Immunology Population Biology Lymphocyte Activation Lymphocyte Depletion Article Mice Antigen Cell Line Tumor Neoplasms hemic and lymphatic diseases Antibodies Bispecific Gene Order medicine Animals Humans Immunology and Allergy Cytotoxic T cell education CD20 B-Lymphocytes education.field_of_study Histocompatibility Antigens Class I Immunotherapy Antigens CD20 Molecular biology Disease Models Animal CTL Cytokine Oncology biology.protein Antibody Peptides Protein Binding Single-Chain Antibodies T-Lymphocytes Cytotoxic |
| Zdroj: | Cancer Immunology, Immunotherapy. 62:1093-1105 |
| ISSN: | 1432-0851 0340-7004 |
| DOI: | 10.1007/s00262-013-1408-8 |
| Popis: | Attempts to generate robust anti-tumour cytotoxic T lymphocyte (CTL) responses using immunotherapy are frequently thwarted by exhaustion and anergy of CTL recruited to tumour. One strategy to overcome this is to retarget a population of virus-specific CTL to kill tumour cells. Here, we describe a proof-of-principle study using a bispecific conjugate designed to retarget ovalbumin (OVA)-specific CTL to kill tumour cells via CD20. A single-chain trimer (SCT) consisting of MHCI H-2K(b)/SIINFEKL peptide/beta 2 microglobulin/BirA was expressed in bacteria, refolded and chemically conjugated to one (1:1; F2) or two (2:1; F3) anti-hCD20 Fab' fragments. In vitro, the [SCT × Fab'] (F2 and F3) redirected SIINFEKL-specific OT-I CTL to kill CD20(+) target cells, and in the presence of CD20(+) target cells to provide crosslinking, they were also able to induce proliferation of OT-I cells. In vivo, activated OT-I CTL could be retargeted to kill [SCT × Fab']-coated B cells from hCD20 transgenic (hCD20 Tg) mice and also EL4 and B16 mouse tumour cells expressing human CD20 (hCD20). Importantly, in a hCD20 Tg mouse model, [SCT × Fab'] administered systemically were able to retarget activated OT-I cells to deplete normal B cells, and their performance matched that of a bispecific antibody (BsAb) comprising anti-CD3 and anti-CD20. [SCT × Fab'] were also active therapeutically in an EL4 tumour model. Furthermore, measurement of serum cytokine levels suggests that [SCT × Fab'] are associated with a lower level of inflammatory cytokine release than the BsAb and so may be advantageous clinically in terms of reduced toxicity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink