Abstract
High-affinity folate receptors (FRs) are expressed at elevated levels on many human tumors. Bispecific antibodies that bind the FR and the T-cell receptor (TCR) mediate lysis of these tumor cells by cytotoxic T lymphocytes. In this report, conjugates that consist of folate covalently linked to anti- TCR antibodies are shown to be potent in mediating lysis of tumor cells that express either the α or β isoform of the FR. Intact antibodies with an average of five folates per molecule exhibited high affinity for FR+ tumor cells but did not bind to FR- tumor cells. Lysis of FR+ cell lines could be detected at concentrations as low as 1 pM (≃0.1 ng/ml), which was 1/1000th the concentration required to detect binding to the FR+ cells. Various FR+ mouse tumor cell lines could be targeted with each of three different anti- TCR antibodies that were tested as conjugates. The antibodies included 1B2, a clonotypic antibody specific for the cytotoxic T cell clone 2C; KJ16, an anti-Vβ8 antibody; and 2C11, an anti-CD3 antibody. These antibodies differ in affinities by up to 100-fold, yet the cytolytic capabilities of the folate/antibody conjugates differed by no more than 10-fold. The reduced size (in comparison with bispecific antibodies) and high affinity of folate conjugates suggest that they may be useful as immunotherapeutic agents in targeting tumors that express folate receptors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 9057-9061 |
| Number of pages | 5 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 92 |
| Issue number | 20 |
| DOIs | |
| State | Published - Sep 26 1995 |
Fingerprint
ASJC Scopus subject areas
- General
Cite this
Conjugates of folate and anti-T-cell-receptor antibodies specifically target folate-receptor-positive tumor cells for lysis. / Kranz, David M.; Patrick, Todd A.; Brigle, Kevin E.; Spinella, Michael J.; Roy, Edward J.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 20, 26.09.1995, p. 9057-9061.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Conjugates of folate and anti-T-cell-receptor antibodies specifically target folate-receptor-positive tumor cells for lysis
AU - Kranz, David M.
AU - Patrick, Todd A.
AU - Brigle, Kevin E.
AU - Spinella, Michael J.
AU - Roy, Edward J.
PY - 1995/9/26
Y1 - 1995/9/26
N2 - High-affinity folate receptors (FRs) are expressed at elevated levels on many human tumors. Bispecific antibodies that bind the FR and the T-cell receptor (TCR) mediate lysis of these tumor cells by cytotoxic T lymphocytes. In this report, conjugates that consist of folate covalently linked to anti- TCR antibodies are shown to be potent in mediating lysis of tumor cells that express either the α or β isoform of the FR. Intact antibodies with an average of five folates per molecule exhibited high affinity for FR+ tumor cells but did not bind to FR- tumor cells. Lysis of FR+ cell lines could be detected at concentrations as low as 1 pM (≃0.1 ng/ml), which was 1/1000th the concentration required to detect binding to the FR+ cells. Various FR+ mouse tumor cell lines could be targeted with each of three different anti- TCR antibodies that were tested as conjugates. The antibodies included 1B2, a clonotypic antibody specific for the cytotoxic T cell clone 2C; KJ16, an anti-Vβ8 antibody; and 2C11, an anti-CD3 antibody. These antibodies differ in affinities by up to 100-fold, yet the cytolytic capabilities of the folate/antibody conjugates differed by no more than 10-fold. The reduced size (in comparison with bispecific antibodies) and high affinity of folate conjugates suggest that they may be useful as immunotherapeutic agents in targeting tumors that express folate receptors.
AB - High-affinity folate receptors (FRs) are expressed at elevated levels on many human tumors. Bispecific antibodies that bind the FR and the T-cell receptor (TCR) mediate lysis of these tumor cells by cytotoxic T lymphocytes. In this report, conjugates that consist of folate covalently linked to anti- TCR antibodies are shown to be potent in mediating lysis of tumor cells that express either the α or β isoform of the FR. Intact antibodies with an average of five folates per molecule exhibited high affinity for FR+ tumor cells but did not bind to FR- tumor cells. Lysis of FR+ cell lines could be detected at concentrations as low as 1 pM (≃0.1 ng/ml), which was 1/1000th the concentration required to detect binding to the FR+ cells. Various FR+ mouse tumor cell lines could be targeted with each of three different anti- TCR antibodies that were tested as conjugates. The antibodies included 1B2, a clonotypic antibody specific for the cytotoxic T cell clone 2C; KJ16, an anti-Vβ8 antibody; and 2C11, an anti-CD3 antibody. These antibodies differ in affinities by up to 100-fold, yet the cytolytic capabilities of the folate/antibody conjugates differed by no more than 10-fold. The reduced size (in comparison with bispecific antibodies) and high affinity of folate conjugates suggest that they may be useful as immunotherapeutic agents in targeting tumors that express folate receptors.
UR - http://www.scopus.com/inward/record.url?scp=0029073423&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029073423&partnerID=8YFLogxK
U2 - 10.1073/pnas.92.20.9057
DO - 10.1073/pnas.92.20.9057
M3 - Article
C2 - 7568072
AN - SCOPUS:0029073423
VL - 92
SP - 9057
EP - 9061
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 20
ER -