Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows
In vitro assessments for the prediction of pharmacokinetic (PK) behavior of biotherapeutics can help identify corresponding liabilities significantly earlier in the discovery timeline. This can minimize the need for extensive early in vivo PK characterization, thereby reducing animal usage and optim...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2384104 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832576538142310400 |
|---|---|
| author | Tushar Jain Bianka Prinz Alexander Marker Alexander Michel Katrin Reichel Valerie Czepczor Sylvie Klieber Wei Sun Sagar Kathuria Sevim Oezguer Bruederle Christian Lange Lena Wahl Charles Starr Alessandro Masiero Lindsay Avery |
| author_facet | Tushar Jain Bianka Prinz Alexander Marker Alexander Michel Katrin Reichel Valerie Czepczor Sylvie Klieber Wei Sun Sagar Kathuria Sevim Oezguer Bruederle Christian Lange Lena Wahl Charles Starr Alessandro Masiero Lindsay Avery |
| author_sort | Tushar Jain |
| collection | DOAJ |
| description | In vitro assessments for the prediction of pharmacokinetic (PK) behavior of biotherapeutics can help identify corresponding liabilities significantly earlier in the discovery timeline. This can minimize the need for extensive early in vivo PK characterization, thereby reducing animal usage and optimizing resources. In this study, we recommend bolstering classical developability workflows with in vitro measures correlated with PK. In agreement with current literature, in vitro measures assessing nonspecific interactions, self-interaction, and FcRn interaction are demonstrated to have the highest correlations to clearance in hFcRn Tg32 mice. Crucially, the dataset used in this study has broad sequence diversity and a range of physicochemical properties, adding robustness to our recommendations. Finally, we demonstrate a computational approach that combines multiple in vitro measurements with a multivariate regression model to improve the correlation to PK compared to any individual assessment. Our work demonstrates that a judicious choice of high throughput in vitro measurements and computational predictions enables the prioritization of candidate molecules with desired PK properties. |
| format | Article |
| id | doaj-art-38817983990a4fd685f565a20d0c4cd1 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-38817983990a4fd685f565a20d0c4cd12025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2384104Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflowsTushar Jain0Bianka Prinz1Alexander Marker2Alexander Michel3Katrin Reichel4Valerie Czepczor5Sylvie Klieber6Wei Sun7Sagar Kathuria8Sevim Oezguer Bruederle9Christian Lange10Lena Wahl11Charles Starr12Alessandro Masiero13Lindsay Avery14Department of Computational Biology, Adimab LLC, Mountain View, CA, USADepartment of Antibody Discovery, Adimab LLC, Lebanon, NH, USADepartment of Drug Metabolism and Pharmacokinetics, Sanofi, Frankfurt, GermanyDepartment of Drug Metabolism and Pharmacokinetics, Sanofi, Cambridge, MA, USADepartment of Large Molecule Research, Sanofi, Frankfurt, GermanyDepartment of Drug Metabolism and Pharmacokinetics, Sanofi, Paris, FranceDepartment of Drug Metabolism and Pharmacokinetics, Sanofi, Paris, FranceDepartment of Drug Metabolism and Pharmacokinetics, Sanofi, Cambridge, MA, USADepartment of Large Molecule Research, Sanofi, Cambridge, MA, USADepartment of Large Molecule Research, Sanofi, Frankfurt, GermanyDepartment of Large Molecule Research, Sanofi, Frankfurt, GermanyDepartment of Large Molecule Research, Sanofi, Frankfurt, GermanySanofi, Global CMC Development, Framingham, MA, USADepartment of Large Molecule Research, Sanofi, Paris, FranceDepartment of Drug Metabolism and Pharmacokinetics, Sanofi, Cambridge, MA, USAIn vitro assessments for the prediction of pharmacokinetic (PK) behavior of biotherapeutics can help identify corresponding liabilities significantly earlier in the discovery timeline. This can minimize the need for extensive early in vivo PK characterization, thereby reducing animal usage and optimizing resources. In this study, we recommend bolstering classical developability workflows with in vitro measures correlated with PK. In agreement with current literature, in vitro measures assessing nonspecific interactions, self-interaction, and FcRn interaction are demonstrated to have the highest correlations to clearance in hFcRn Tg32 mice. Crucially, the dataset used in this study has broad sequence diversity and a range of physicochemical properties, adding robustness to our recommendations. Finally, we demonstrate a computational approach that combines multiple in vitro measurements with a multivariate regression model to improve the correlation to PK compared to any individual assessment. Our work demonstrates that a judicious choice of high throughput in vitro measurements and computational predictions enables the prioritization of candidate molecules with desired PK properties.https://www.tandfonline.com/doi/10.1080/19420862.2024.2384104Antibodiesbiotherapeuticsdevelopabilityin silico predictionin vitro measurementin vivo assessment |
| spellingShingle | Tushar Jain Bianka Prinz Alexander Marker Alexander Michel Katrin Reichel Valerie Czepczor Sylvie Klieber Wei Sun Sagar Kathuria Sevim Oezguer Bruederle Christian Lange Lena Wahl Charles Starr Alessandro Masiero Lindsay Avery Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows mAbs Antibodies biotherapeutics developability in silico prediction in vitro measurement in vivo assessment |
| title | Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows |
| title_full | Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows |
| title_fullStr | Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows |
| title_full_unstemmed | Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows |
| title_short | Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows |
| title_sort | assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows |
| topic | Antibodies biotherapeutics developability in silico prediction in vitro measurement in vivo assessment |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2384104 |
| work_keys_str_mv | AT tusharjain assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT biankaprinz assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT alexandermarker assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT alexandermichel assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT katrinreichel assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT valerieczepczor assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT sylvieklieber assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT weisun assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT sagarkathuria assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT sevimoezguerbruederle assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT christianlange assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT lenawahl assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT charlesstarr assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT alessandromasiero assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows AT lindsayavery assessmentandincorporationofinvitrocorrelatestopharmacokineticoutcomesinantibodydevelopabilityworkflows |