Hyaluronic Acid–Antibody Fragment Bioconjugates for Extended Ocular Pharmacokinetics

Famili, Amin; Crowell, Susan; Loyet, Kelly M.; Mandikian, Danielle; Boswell, C. Andrew; Cain, David; Chan, Joyce; Comps-Agrar, Laëtitia; Kamath, Amrita V.; Rajagopal, Karthikan

doi:10.1021/acs.bioconjchem.9b00475

Cited by 13 publications

(8 citation statements)

References 32 publications

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“…Most approaches currently pursued for ocular half-life extension aim to reduce the drug’s diffusivity. This may be accomplished by binding to a vitreous matrix constituent, such as hyaluronic acid or collagen [ 19 , 20 ], by designing a bulky format of large hydrodynamic radius [ 14 , 15 , 16 , 17 ] or by enabling it to associate with soluble endogenous macromolecules, such as albumin, and form high MW complexes.…”

Section: Discussionmentioning

confidence: 99%

“…A HSA binding immunoglobulin single variable domain (nanobody, VHH) sequence (ALB8 from WO 2012/131078 A1 [ 33 ]) was recombinantly fused via a 3× GGGGS-linker to the C-terminus of the heavy chain of a species-matched rabbit Fab (rabFab) [ 17 ]. The C-terminus of the nanobody was modified by a His6-tag (FabA).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, durability can be enhanced by reducing the rate of ocular elimination, which is driven by diffusion from the vitreous body to the anterior chamber and by aqueous humor (AH) turnover [ 12 ]. Diffusivity decreases inversely with macromolecular size, so larger antibody formats, PEGylation or conjugation to biopolymers result in prolonged ocular retention [ 13 , 14 , 15 , 16 , 17 , 18 ]. This may also be achieved with binding to constituents of the vitreous matrix, such as collagen (type II) and hyaluronic acid [ 19 , 20 ], or association with soluble proteins, like albumin [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin

et al. 2020

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The burden associated with frequent injections of current intravitreal (IVT) therapeutics may be reduced by long-acting delivery strategies. Binding to serum albumin has been shown to extend the ocular half-life in rabbits, however, the underlying molecular mechanisms and translational relevance remain unclear. The aim of this work was to characterize the in vitro and in vivo formation of complexes between human serum albumin (HSA) and an antigen-binding fragment of a rabbit antibody linked to an anti-HSA nanobody (FabA). The ocular and systemic pharmacokinetics of 3H-labeled FabA (0.05 mg/eye IVT) co-formulated with HSA (1 and 15 nmol/eye) were assessed in Dutch belted rabbits. Next, FabA was incubated in vitreous samples from cynomolgus monkeys and human donors (healthy and diseased) supplemented with species-specific serum albumin. Finally, the FabA-albumin complexes formed in vitro and in vivo were analyzed by radio-size exclusion chromatography. A 3-fold increase in FabA vitreal exposure and half-life was observed in rabbits co-administered with 15 nmol HSA compared to 1 nmol and a control arm. The different pharmacokinetic behavior was explained with the formation of higher molecular weight FabA–albumin complexes. The analysis of vitreous samples revealed the existence of predominantly 1:1 complexes at endogenous or low concentrations of supplemented albumin. A shift towards 1:2 complexes was observed with increasing albumin concentrations. Overall, these results suggest that endogenous vitreal albumin concentrations are insufficient for half-life extension and warrant supplementation in the dosing formulation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin

et al. 2020

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“…This resulted in a tenfold increase in the drug half-life with no change in pharmacological activity. Famili et al [31] developed hyaluronic acid-fragment antigen-binding (Fab) bioconjugates for anti-VEGF therapies. They found that conjugation of Fab with negatively charged hyaluronic acid significantly slowed in vivo clearance from rabbit vitreous humor after intravitreal injection.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Novel Succinyl Chitosan-Dexamethasone Conjugates for Potential Intravitreal Dexamethasone Delivery

Dubashynskaya

Bokatyi

Головкин

et al. 2021

IJMS

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The development of intravitreal glucocorticoid delivery systems is a current global challenge for the treatment of inflammatory diseases of the posterior segment of the eye. The main advantages of these systems are that they can overcome anatomical and physiological ophthalmic barriers and increase local bioavailability while prolonging and controlling drug release over several months to improve the safety and effectiveness of glucocorticoid therapy. One approach to the development of optimal delivery systems for intravitreal injections is the conjugation of low-molecular-weight drugs with natural polymers to prevent their rapid elimination and provide targeted and controlled release. This study focuses on the development of a procedure for a two-step synthesis of dexamethasone (DEX) conjugates based on the natural polysaccharide chitosan (CS). We first used carbodiimide chemistry to conjugate DEX to CS via a succinyl linker, and we then modified the obtained systems with succinic anhydride to impart a negative ζ-potential to the polymer particle surface. The resulting polysaccharide carriers had a degree of substitution with DEX moieties of 2–4%, a DEX content of 50–85 μg/mg, and a degree of succinylation of 64–68%. The size of the obtained particles was 400–1100 nm, and the z-potential was −30 to −33 mV. In vitro release studies at pH 7.4 showed slow hydrolysis of the amide and ester bonds in the synthesized systems, with a total release of 8–10% for both DEX and succinyl dexamethasone (SucDEX) after 1 month. The developed conjugates showed a significant anti-inflammatory effect in TNFα-induced and LPS-induced inflammation models, suppressing CD54 expression in THP-1 cells by 2- and 4-fold, respectively. Thus, these novel succinyl chitosan-dexamethasone (SucCS-DEX) conjugates are promising ophthalmic carriers for intravitreal delivery.

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“…1−3 Driven by the technological advances in material science and medical devices, various LA delivery systems have been applied in the treatment and prevention of diseases. 4,5 LA drug products consist of a range of mature and emerging delivery platforms, including polymer based micro-and nano-particulate systems, 5−7 polymeric implants, 8,9 in-situ forming hydrogels, 10−12 polymer-solvent depots, 13 polymer drug conjugates 14 and lipid-based liquid crystals 15,16 for subdermal insertion. Polymer matrices, lipid systems, and matrices formed by self-assembling active pharmaceutical ingredient (API) 17 are also used to achieve extended drug release owning to their unique physical properties.…”

Section: Introductionmentioning

confidence: 99%

Microstructure, Quality, and Release Performance Characterization of Long-Acting Polymer Implant Formulations with X-Ray Microscopy and Quantitative AI Analytics

Nagapudi¹,

Zhu

Chang³

et al. 2021

Journal of Pharmaceutical Sciences

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Long-acting implants are typically formulated using carrier(s) with specific physical and chemical properties, along with the active pharmaceutical ingredient (API), to achieve the desired daily exposure for the target duration of action. In characterizing such formulations, real-time in-vitro and in-vivo experiments that are typically used to characterize implants are lengthy, costly, and labor intensive as these implants are designed to be long acting. A novel characterization technique, combining high resolution three-dimensional X-Ray microscopy imaging, image-based quantification, and transport simulation, has been employed to provide a mechanistic understanding of formulation and process impact on the microstructures and performance of a polymer-based implant. Artificial intelligence-based image segmentation and image data analytics were used to convert morphological features visualized at high resolution into numerical microstructure models. These digital models were then used to calculate key physical parameters governing drug transport in a polymer matrix, including API uniformity, API domain size, and permeability. This powerful new tool has the potential to advance the mechanistic understanding of the interplay between drug-microstructure and performance and accelerate the therapeutic development long-acting implants.

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Hyaluronic Acid–Antibody Fragment Bioconjugates for Extended Ocular Pharmacokinetics

Cited by 13 publications

References 32 publications

Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin

Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin

Synthesis and Characterization of Novel Succinyl Chitosan-Dexamethasone Conjugates for Potential Intravitreal Dexamethasone Delivery

Microstructure, Quality, and Release Performance Characterization of Long-Acting Polymer Implant Formulations with X-Ray Microscopy and Quantitative AI Analytics

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