Bispecific agents target endogenous murine T cells against human tumor xenografts.
A variety of immunological approaches to cancer treatment are currently being explored. These include strategies designed to enhance or redirect the activity of T cells against tumors. Bispecific antibodies comprise a class of agents capable of redirecting T cells by binding to a tumor antigen and the T-cell receptor (TCR). In vivo pre-clinical testing of bispecific antibodies against human tumors has to date been limited to the use of immunodeficient mice that receive the bispecific agent, activated human effector T cells, and human tumor cells. In this report, we show that TCR transgenic/RAG-1 knockout mice (TCR/RAG) serve as a unique model allowing endogenous T cells to be redirected against transplanted human tumors. The findings show that TCR/RAG mice (i) accepted transplants of human tumors, including the folate-receptor-positive tumor line KB; (ii) contained endogenous cytotoxic T lymphocytes that could be activated in vivo with an antigenic peptide recognized by the transgenic TCR; (iii) rejected human tumors after treatment with the activating peptide and bispecific agents that contained folic acid co-valently linked to an anti-TCR antibody. Successful rejection was achieved with folate conjugates of Fab or scFv fragments. Treatment with activating agents and bispecific conjugates resulted in the complete eradication of freshly transplanted tumors as well as significantly prolonging the survival of mice bearing established solid tumors. Our results highlight the importance of including T-cell-activating modalities in combination with bispecific antibodies. Additionally, we introduce a system that allows endogenous T cells to be redirected against human tumor xenografts and in which the T cells may be followed in vivo by use of a clonotypic marker.
Rund
L A
LA
Department of Biochemistry, University of Illinois, Urbana, IL 61801-3792, USA.
Cho
B K
BK
Manning
T C
TC
Holler
P D
PD
Roy
E J
EJ
Kranz
D M
DM
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology*; D019496:Cancer Vaccines; D002294:Carcinoma, Squamous Cell / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005434:Flow Cytometry; D058973:Folate Receptors, GPI-Anchored; D016654:Genes, RAG-1 / Q000276:immunology; D019672:Genes, T-Cell Receptor / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011956:Receptors, Cell Surface; D013601:T-Lymphocytes / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D019496:Cancer Vaccines; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D011956:Receptors, Cell Surface