Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies
A variety of Fc domain engineering approaches for abrogating the effector functions of mAbs exists. To address some of the limitations of the current Fc domain silencing approaches, we are exploring a less commonly considered option which relies on the deletion of the hinge. Removal of the hinge dom...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-09-01
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| Series: | Antibodies |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4468/9/4/50 |
| _version_ | 1797552750551105536 |
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| author | Jamie Valeich Dan Boyd Manu Kanwar Daniel Stenzel Deblina De Ghosh Arpa Ebrahimi James Woo Jenny Wang Alexandre Ambrogelly |
| author_facet | Jamie Valeich Dan Boyd Manu Kanwar Daniel Stenzel Deblina De Ghosh Arpa Ebrahimi James Woo Jenny Wang Alexandre Ambrogelly |
| author_sort | Jamie Valeich |
| collection | DOAJ |
| description | A variety of Fc domain engineering approaches for abrogating the effector functions of mAbs exists. To address some of the limitations of the current Fc domain silencing approaches, we are exploring a less commonly considered option which relies on the deletion of the hinge. Removal of the hinge domain in humanized IgG1 and IgG4 mAbs obliterates their ability to bind to activating human Fc gamma receptors I and IIIA, while leaving their ability to engage their target antigen intact. Deletion of the hinge also reduces binding to the Fc neonatal receptor, although Fc engineering allows partial recovery of affinity. Engineering of the CH3 domain, stabilizes hinge deleted IgG4s and prevents Fab arm exchange. The faster clearing properties together with the pacified Fc make modality of the hinge deleted mAb an appealing solution for therapeutic and diagnostic applications. |
| first_indexed | 2024-03-10T16:05:34Z |
| format | Article |
| id | doaj.art-536aa11a0895400d9b3bf9dacf2aa0f6 |
| institution | Directory Open Access Journal |
| issn | 2073-4468 |
| language | English |
| last_indexed | 2024-03-10T16:05:34Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibodies |
| spelling | doaj.art-536aa11a0895400d9b3bf9dacf2aa0f62023-11-20T14:52:34ZengMDPI AGAntibodies2073-44682020-09-01945010.3390/antib9040050Taking the Hinge off: An Approach to Effector-Less Monoclonal AntibodiesJamie Valeich0Dan Boyd1Manu Kanwar2Daniel Stenzel3Deblina De Ghosh4Arpa Ebrahimi5James Woo6Jenny Wang7Alexandre Ambrogelly8Pharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAPharmaceutical & Biologics Development, Gilead Sciences, 4010 Ocean Ranch Blvd, Oceanside, CA 92056, USAA variety of Fc domain engineering approaches for abrogating the effector functions of mAbs exists. To address some of the limitations of the current Fc domain silencing approaches, we are exploring a less commonly considered option which relies on the deletion of the hinge. Removal of the hinge domain in humanized IgG1 and IgG4 mAbs obliterates their ability to bind to activating human Fc gamma receptors I and IIIA, while leaving their ability to engage their target antigen intact. Deletion of the hinge also reduces binding to the Fc neonatal receptor, although Fc engineering allows partial recovery of affinity. Engineering of the CH3 domain, stabilizes hinge deleted IgG4s and prevents Fab arm exchange. The faster clearing properties together with the pacified Fc make modality of the hinge deleted mAb an appealing solution for therapeutic and diagnostic applications.https://www.mdpi.com/2073-4468/9/4/50monoclonal antibodymAbhingeeffector functionAntibody-dependent cellular cytotoxicity (ADCC)IgG4 |
| spellingShingle | Jamie Valeich Dan Boyd Manu Kanwar Daniel Stenzel Deblina De Ghosh Arpa Ebrahimi James Woo Jenny Wang Alexandre Ambrogelly Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies Antibodies monoclonal antibody mAb hinge effector function Antibody-dependent cellular cytotoxicity (ADCC) IgG4 |
| title | Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies |
| title_full | Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies |
| title_fullStr | Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies |
| title_full_unstemmed | Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies |
| title_short | Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies |
| title_sort | taking the hinge off an approach to effector less monoclonal antibodies |
| topic | monoclonal antibody mAb hinge effector function Antibody-dependent cellular cytotoxicity (ADCC) IgG4 |
| url | https://www.mdpi.com/2073-4468/9/4/50 |
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