Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies
Bispecific antibodies (BsAbs) capable of recognizing two distinct epitopes or antigens offer promising therapeutic options for various diseases by targeting multiple pathways. The favorable pharmacokinetic (PK) properties of monoclonal antibodies (mAbs) are crucial, as they directly influence patien...
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| Format: | Article |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2318817 |
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| author | Kristina M.J. Aertker Minu Ravindra Pilvankar Tobias M. Prass Michaela Blech Fabian Higel Srinath Kasturirangan |
| author_facet | Kristina M.J. Aertker Minu Ravindra Pilvankar Tobias M. Prass Michaela Blech Fabian Higel Srinath Kasturirangan |
| author_sort | Kristina M.J. Aertker |
| collection | DOAJ |
| description | Bispecific antibodies (BsAbs) capable of recognizing two distinct epitopes or antigens offer promising therapeutic options for various diseases by targeting multiple pathways. The favorable pharmacokinetic (PK) properties of monoclonal antibodies (mAbs) are crucial, as they directly influence patient safety and therapeutic efficacy. For numerous mAb therapeutics, optimization of neonatal Fc receptor (FcRn) interactions and elimination of unfavorable molecular properties have led to improved PK properties. However, many BsAbs exhibit unfavorable PK, which has precluded their development as drugs. In this report, we present studies on the molecular determinants underlying the distinct PK profiles of three IgG1-scFv BsAbs. Our study indicated that high levels of nonspecific interactions, elevated isoelectric point (pI), and increased number of positively charged patches contributed to the fast clearance of IgG1-scFv. FcRn chromatography results revealed specific scFv-FcRn interactions that are unique to the IgG1-scFv, which was further supported by molecular dynamics (MD) simulation. These interactions likely stabilize the BsAb FcRn interaction at physiological pH, which in turn could disrupt FcRn-mediated BsAb recycling. In addition to the empirical observations, we also evaluated the impact of in silico properties, including pI differential between the Fab and scFv and the ratio of dipole moment to hydrophobic moment (RM) and their correlation with the observed clearance. These findings highlight that the PK properties of BsAbs may be governed by novel determinants, owing to their increased structural complexity compared to immunoglobulin G (IgG) 1 antibodies. |
| format | Article |
| id | doaj-art-1c603c903ef24f8ab169d4e15eb01906 |
| 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-1c603c903ef24f8ab169d4e15eb019062025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2318817Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodiesKristina M.J. Aertker0Minu Ravindra Pilvankar1Tobias M. Prass2Michaela Blech3Fabian Higel4Srinath Kasturirangan5Analytical Development Biologicals, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, GermanyBiotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USACenter for Theoretical Chemistry, Ruhr University Bochum, Bochum, GermanyAnalytical Development Biologicals, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, GermanyGlobal CMC Experts NBE, Global Quality Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, GermanyBiotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USABispecific antibodies (BsAbs) capable of recognizing two distinct epitopes or antigens offer promising therapeutic options for various diseases by targeting multiple pathways. The favorable pharmacokinetic (PK) properties of monoclonal antibodies (mAbs) are crucial, as they directly influence patient safety and therapeutic efficacy. For numerous mAb therapeutics, optimization of neonatal Fc receptor (FcRn) interactions and elimination of unfavorable molecular properties have led to improved PK properties. However, many BsAbs exhibit unfavorable PK, which has precluded their development as drugs. In this report, we present studies on the molecular determinants underlying the distinct PK profiles of three IgG1-scFv BsAbs. Our study indicated that high levels of nonspecific interactions, elevated isoelectric point (pI), and increased number of positively charged patches contributed to the fast clearance of IgG1-scFv. FcRn chromatography results revealed specific scFv-FcRn interactions that are unique to the IgG1-scFv, which was further supported by molecular dynamics (MD) simulation. These interactions likely stabilize the BsAb FcRn interaction at physiological pH, which in turn could disrupt FcRn-mediated BsAb recycling. In addition to the empirical observations, we also evaluated the impact of in silico properties, including pI differential between the Fab and scFv and the ratio of dipole moment to hydrophobic moment (RM) and their correlation with the observed clearance. These findings highlight that the PK properties of BsAbs may be governed by novel determinants, owing to their increased structural complexity compared to immunoglobulin G (IgG) 1 antibodies.https://www.tandfonline.com/doi/10.1080/19420862.2024.2318817Biophysical assessmentbispecific antibodyFcRnin silico developabilitypharmacokinetics (PK) |
| spellingShingle | Kristina M.J. Aertker Minu Ravindra Pilvankar Tobias M. Prass Michaela Blech Fabian Higel Srinath Kasturirangan Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies mAbs Biophysical assessment bispecific antibody FcRn in silico developability pharmacokinetics (PK) |
| title | Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies |
| title_full | Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies |
| title_fullStr | Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies |
| title_full_unstemmed | Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies |
| title_short | Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies |
| title_sort | exploring molecular determinants and pharmacokinetic properties of igg1 scfv bispecific antibodies |
| topic | Biophysical assessment bispecific antibody FcRn in silico developability pharmacokinetics (PK) |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2318817 |
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