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CD3 x CD28 cross-interacting bispecific antibodies improve tumor cell dependent T-cell activation
- Source :
- Cancer immunology, immunotherapy : CII. 54(11)
- Publication Year :
- 2004
-
Abstract
- Bispecific antibodies (Bs-Abs) containing an anti-CD3 and an anti-TAA specificity can recruit T cells to the tumor for cancer immunotherapy. To be effective, efficient activation at the tumor site is a prerequisite. This can be achieved by triggering both the T-cell receptor and the co-stimulatory molecule CD28. We engineered two recombinant cross-interacting Bs-Abs (CriBs-Abs) by incorporating a peptide tag and its cognate single-chain variable fragment (scFv), respectively, into a pair of (tumor × CD3) and (tumor × CD28) binding Bs-Abs. A 30-fold lower concentration of the activating CriBs-Ab as compared to non interacting Bs-Ab was sufficient for strong T-cell activation in the presence of tumor cells. One thousand-fold higher concentrations of both CriBs-Abs were required for marginal T-cell activation (70-fold below maximal response) in the absence of tumor cells. An optimized stoichiometry (1 : 1000) of activating versus co-stimulating CriBs-Ab thus allowed low doses of activating CriBs-Ab to induce tumor-cell dependent T-cell activation when used in combination with high concentrations of the pre-targeted co-stimulating CriBs-Ab in vitro. This indicates a large window of operation in which only tumor cell dependent T-cell activation is induced and systemic tumor cell independent T-cell activation is avoided, while ensuring optimal activation with a low concentration of the activating CriBs-Ab, which has the highest potential to induce toxic effects in vivo.
- Subjects :
- Cancer Research
CD3 Complex
medicine.medical_treatment
CD3
T cell
T-Lymphocytes
Immunology
Lymphocyte Activation
Cell Line
Mice
Cancer immunotherapy
Co-stimulation
CD28 Antigens
Neoplasms
Antibodies, Bispecific
medicine
Immunology and Allergy
Animals
Humans
Receptor
biology
Chemistry
CD28
Immunotherapy
Molecular biology
Cell biology
Mice, Inbred C57BL
medicine.anatomical_structure
Oncology
Cell culture
biology.protein
Female
Subjects
Details
- ISSN :
- 03407004
- Volume :
- 54
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Cancer immunology, immunotherapy : CII
- Accession number :
- edsair.doi.dedup.....af8d95a2483e7a1b69cfe8a03ba68129