Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules

Datta‐Mannan, Amita; Brown, Robert D.; Cain, Paul; Feng, Yiqing

doi:10.3390/antib11010002

Cited by 8 publications

(10 citation statements)

References 37 publications

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“…L19-IFNγ KRG showed excellent in vivo tumor-targeting properties and modest tumor growth retardation, which was enhanced when the product was used in combination with immune checkpoint inhibitors or with standard chemotherapy. The PK profile in monkeys was similar to the one reported for other IgG-based products [ 47 ]. It would be attractive to use a long-lived product (such as IgGs) to reduce dosing frequency in patients.…”

Section: Discussionsupporting

confidence: 80%

An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties

et al. 2023

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Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFNγ to neoplastic lesions may be limited by the trapping of IFNγ-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFNγ with reduced affinity to its cognate receptor. The product (named L19-IFNγ KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFNγ KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1.

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Section: Discussionsupporting

confidence: 80%

An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties

et al. 2023

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“… 5 , 6 The slow clinical success of BsAbs can be attributed to several factors, including increased structural complexity leading to greater challenges in their CMC properties, and in their pharmacokinetic (PK) profiles. 7 , 8 …”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have aimed to understand the reasons for faster clearance and non-linear PK observed with BsAbs. 7 , 8 …”

Section: Introductionmentioning

confidence: 99%

Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies

Aertker,

Pilvankar,

Prass

et al. 2024

mAbs

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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.

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“…Integration of quantitative whole-body biodistribution and tissue level imaging into the development can provide informative readouts regarding the disposition (Boswell et al 2012;Boswell et al 2013;Datta-Mannan 2019;Khawli et al 1996;Khawli et al 2010). Towards this, a handful of imaging approaches including, computed tomography (CT), magnetic resonance imaging, whole-body imaging bioluminescence/radiolabeling and positron emission tomography (PET) have been leveraged (Boswell et al 2013;Datta-Mannan 2019;Datta-Mannan et al 2021;Datta-Mannan A 2016 ;Williams et al 2016;Boswell et al 2019;Datta-Mannan et al 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Like most therapeutics, the causalities of BfAb slow clinical success can be generally related to several factors, including an incomplete understanding of the biologic mechanism of action and exposure–response profiles, insufficient safety margins, strategic industry decisions, and immunogenicity. The higher structural diversity of the BfAbs also results in greater uncertainty in their pharmacokinetic (PK) and disposition profiles that could limit their potential advantages ( Khawli et al, 1996 , 2010 ; Boswell et al, 2012 , 2013 ; Tibbitts et al, 2016 ; Datta-Mannan et al, 2016 , 2019 ; Datta-Mannan et al, 2019 ; Rock and Foti 2019 ; Datta-Mannan et al, 2021 ). As such, consideration of dynamic evaluations of BfAb tissue and cellular biodistribution profiles and how these are connected to their clearance are warranted.…”

Section: Introductionmentioning

confidence: 99%

Intravital Microscopy Reveals Unforeseen Biodistribution Within the Liver and Kidney Mechanistically Connected to the Clearance of a Bifunctional Antibody

et al. 2022

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Bifunctional antibody therapeutics offer the potential for novel functionalities beyond those of the individual mono-specific entities. However, combining these entities into a single molecule can have unpredictable effects, including changes in pharmacokinetics that limit the compound's therapeutic profile. A better understanding of how molecular modifications impact in vivo tissue interactions could help inform bifunctional antibody design. The present studies were predicated on the observation that a bifunctional antibody (BfAb) designed to have minimal off-target interactions cleared from the circulation twice as fast as the monoclonal antibody (mAb) from which it was derived. The present study leverages the spatial and temporal resolution of intravital microscopy (IVM) to identify cellular interactions that may explain the different pharmacokinetics of the two compounds. Disposition studies of mice demonstrated that radiolabeled compounds distributed similarly over the first 24 hours, except that BfAb accumulated ~2-3-fold more than mAb in the liver.IVM studies of mice demonstrated that both distributed to endosomes of liver endothelia, but with different kinetics; whereas mAb accumulated rapidly within the first hour of administration, BfAb accumulated only modestly during the first hour, but continued to accumulate over 24 hours, ultimately reaching levels similar to those of the mAb. Although neither compound was freely filtered by the mouse or rat kidney, BfAb (but not mAb) was found to accumulate over 24 hours in endosomes of proximal tubule cells. These studies demonstrate how IVM can be used as a tool in drug design, revealing unpredicted cellular interactions that are undetectable by conventional analyses.

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Pharmacokinetic Developability and Disposition Profiles of Bispecific Antibodies: A Case Study with Two Molecules

Cited by 8 publications

References 37 publications

An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties

An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties

Exploring molecular determinants and pharmacokinetic properties of IgG1-scFv bispecific antibodies

Intravital Microscopy Reveals Unforeseen Biodistribution Within the Liver and Kidney Mechanistically Connected to the Clearance of a Bifunctional Antibody

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