Electrostatic properties of human germlines and biodistribution of small biologics
Off-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicit...
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/10.1080/19420862.2024.2311991 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832576623982936064 |
|---|---|
| author | Leticia Maria De Souza Cordeiro Kelley Christine Atkinson Argin Aivazian Patrick Frank Joyce Fang Jia Alessandro Mascioni |
| author_facet | Leticia Maria De Souza Cordeiro Kelley Christine Atkinson Argin Aivazian Patrick Frank Joyce Fang Jia Alessandro Mascioni |
| author_sort | Leticia Maria De Souza Cordeiro |
| collection | DOAJ |
| description | Off-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicities. Renal and hepatic uptakes are known to be affected by protein electrostatics, which promote protein internalization through pinocytosis. Using minibodies as a model of an antibody fragment lacking FcRn recycling, we compared the biodistributions of leads with different degrees of accumulation at the kidney and liver. We identified a positive electrostatic patch highly conserved in a germline family very commonly used in the humanization of approved biologics. Neutralization of this patch led to a drastic reduction in the kidney uptake, leading to a biodistribution more favorable to the delivery of highly cytotoxic payloads. Next, we conducted a high throughput study of the electrostatic properties for all combinations of VH and VL germlines. This analysis shows how different VH/VL combinations exhibit varying tendencies to create electrostatic patches, resulting in Fv variants with different isoelectric points. Our work emphasizes the importance of carefully selecting germlines for humanization with optimal electrostatic properties in order to control the unspecific tissue uptake of low molecular weight biologics. |
| format | Article |
| id | doaj-art-70311d3d906a489e9c94e288bac59a19 |
| 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-70311d3d906a489e9c94e288bac59a192025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2311991Electrostatic properties of human germlines and biodistribution of small biologicsLeticia Maria De Souza Cordeiro0Kelley Christine Atkinson1Argin Aivazian2Patrick Frank Joyce3Fang Jia4Alessandro Mascioni5Preclinical discovery, ImaginAb, Inc, Inglewood, CA, USAPreclinical discovery, ImaginAb, Inc, Inglewood, CA, USAPreclinical discovery, ImaginAb, Inc, Inglewood, CA, USACell biology, Skye Biologics, El Segundo, CA, USAPreclinical discovery, ImaginAb, Inc, Inglewood, CA, USAPreclinical discovery, ImaginAb, Inc, Inglewood, CA, USAOff-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicities. Renal and hepatic uptakes are known to be affected by protein electrostatics, which promote protein internalization through pinocytosis. Using minibodies as a model of an antibody fragment lacking FcRn recycling, we compared the biodistributions of leads with different degrees of accumulation at the kidney and liver. We identified a positive electrostatic patch highly conserved in a germline family very commonly used in the humanization of approved biologics. Neutralization of this patch led to a drastic reduction in the kidney uptake, leading to a biodistribution more favorable to the delivery of highly cytotoxic payloads. Next, we conducted a high throughput study of the electrostatic properties for all combinations of VH and VL germlines. This analysis shows how different VH/VL combinations exhibit varying tendencies to create electrostatic patches, resulting in Fv variants with different isoelectric points. Our work emphasizes the importance of carefully selecting germlines for humanization with optimal electrostatic properties in order to control the unspecific tissue uptake of low molecular weight biologics.https://www.tandfonline.com/doi/10.1080/19420862.2024.2311991Antibodyantibody drug conjugateantibody engineeringbiodistributionbiologicselectrostatics |
| spellingShingle | Leticia Maria De Souza Cordeiro Kelley Christine Atkinson Argin Aivazian Patrick Frank Joyce Fang Jia Alessandro Mascioni Electrostatic properties of human germlines and biodistribution of small biologics mAbs Antibody antibody drug conjugate antibody engineering biodistribution biologics electrostatics |
| title | Electrostatic properties of human germlines and biodistribution of small biologics |
| title_full | Electrostatic properties of human germlines and biodistribution of small biologics |
| title_fullStr | Electrostatic properties of human germlines and biodistribution of small biologics |
| title_full_unstemmed | Electrostatic properties of human germlines and biodistribution of small biologics |
| title_short | Electrostatic properties of human germlines and biodistribution of small biologics |
| title_sort | electrostatic properties of human germlines and biodistribution of small biologics |
| topic | Antibody antibody drug conjugate antibody engineering biodistribution biologics electrostatics |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2311991 |
| work_keys_str_mv | AT leticiamariadesouzacordeiro electrostaticpropertiesofhumangermlinesandbiodistributionofsmallbiologics AT kelleychristineatkinson electrostaticpropertiesofhumangermlinesandbiodistributionofsmallbiologics AT arginaivazian electrostaticpropertiesofhumangermlinesandbiodistributionofsmallbiologics AT patrickfrankjoyce electrostaticpropertiesofhumangermlinesandbiodistributionofsmallbiologics AT fangjia electrostaticpropertiesofhumangermlinesandbiodistributionofsmallbiologics AT alessandromascioni electrostaticpropertiesofhumangermlinesandbiodistributionofsmallbiologics |