Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity
CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the r...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2015-12-01
|
| Series: | Antibodies |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2073-4468/4/4/426 |
| _version_ | 1819155672788369408 |
|---|---|
| author | Ulrich Wuellner Kristina Klupsch Fabian Buller Isabella Attinger-Toller Roger Santimaria Irene Zbinden Patricia Henne Dragan Grabulovski Julian Bertschinger Simon Brack |
| author_facet | Ulrich Wuellner Kristina Klupsch Fabian Buller Isabella Attinger-Toller Roger Santimaria Irene Zbinden Patricia Henne Dragan Grabulovski Julian Bertschinger Simon Brack |
| author_sort | Ulrich Wuellner |
| collection | DOAJ |
| description | CD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors. |
| first_indexed | 2024-12-22T15:40:42Z |
| format | Article |
| id | doaj.art-ace5b95010614b2c9dd9d0be87c5386d |
| institution | Directory Open Access Journal |
| issn | 2073-4468 |
| language | English |
| last_indexed | 2024-12-22T15:40:42Z |
| publishDate | 2015-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibodies |
| spelling | doaj.art-ace5b95010614b2c9dd9d0be87c5386d2022-12-21T18:21:08ZengMDPI AGAntibodies2073-44682015-12-014442644010.3390/antib4040426antib4040426Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor SelectivityUlrich Wuellner0Kristina Klupsch1Fabian Buller2Isabella Attinger-Toller3Roger Santimaria4Irene Zbinden5Patricia Henne6Dragan Grabulovski7Julian Bertschinger8Simon Brack9Covagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCovagen AG, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, Wagistrasse 25, 8952 Schlieren, SwitzerlandCD3 bispecific therapies retargeting T cells to tumors have recently demonstrated striking activity in patients. Several CD3 bispecific antibodies directed against various tumor targets are currently being investigated in the clinic across different tumors. One limitation of these therapies is the risk of target-related toxicity due to low-level expression of tumor antigen in normal tissue. In this study we have engineered a bispecific CD3/HER2 FynomAb, COVA420, which redirects T cells with high potency and selectivity to tumor cells with high HER2 expression in vitro and in vivo. COVA420 activity depends on high HER2 density as no activity was observed on cells with lower HER2 levels as found in human normal tissue. These results suggest that COVA420 may spare normal tissue expressing low levels of HER2 while still having uncompromised efficacy on tumor cells with high HER2 expression. This concept may be applied to other cancer antigens that otherwise cannot be targeted by T cell redirecting approaches, and may therefore expand the applicability of CD3 bispecific FynomAbs to a larger number of solid tumors.http://www.mdpi.com/2073-4468/4/4/426FynomAbFynomerbispecific antibodyT cell retargetingoncologyCD3HER2selectivitytoxicity |
| spellingShingle | Ulrich Wuellner Kristina Klupsch Fabian Buller Isabella Attinger-Toller Roger Santimaria Irene Zbinden Patricia Henne Dragan Grabulovski Julian Bertschinger Simon Brack Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity Antibodies FynomAb Fynomer bispecific antibody T cell retargeting oncology CD3 HER2 selectivity toxicity |
| title | Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity |
| title_full | Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity |
| title_fullStr | Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity |
| title_full_unstemmed | Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity |
| title_short | Bispecific CD3/HER2 Targeting FynomAb Induces Redirected T Cell-Mediated Cytolysis with High Potency and Enhanced Tumor Selectivity |
| title_sort | bispecific cd3 her2 targeting fynomab induces redirected t cell mediated cytolysis with high potency and enhanced tumor selectivity |
| topic | FynomAb Fynomer bispecific antibody T cell retargeting oncology CD3 HER2 selectivity toxicity |
| url | http://www.mdpi.com/2073-4468/4/4/426 |
| work_keys_str_mv | AT ulrichwuellner bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT kristinaklupsch bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT fabianbuller bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT isabellaattingertoller bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT rogersantimaria bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT irenezbinden bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT patriciahenne bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT dragangrabulovski bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT julianbertschinger bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity AT simonbrack bispecificcd3her2targetingfynomabinducesredirectedtcellmediatedcytolysiswithhighpotencyandenhancedtumorselectivity |