Modulating pharmacokinetics of an anti-interleukin-8 F(ab′)2 by amine-specific PEGylation with preserved bioactivity

Koumenis, Iphigenia L.; Shahrokh, Zahra; Leong, Steven R.; Hsei, Vanessa; DeForge, Laura; Zapata, Gerardo

doi:10.1016/s0378-5173(99)00458-5

Cited by 49 publications

(37 citation statements)

References 18 publications

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“…3; Table 1). The pharmacokinetic parameters for the Li81 mAb, Fab2, Fab, and PEG-Fab (Table 1) agree with published parameters reported for similar biologics constructs (Koumenis et al, 2000;Leong et al, 2006;Kontermann, 2009;Pepinsky et al, 2011). C max levels of 27, 13, 3.7, and 27 g/ml were observed for the Li81 mAb, Fab2, Fab, and PEG-Fab, respectively.…”

Section: Resultssupporting

confidence: 88%

“…All of the modalities exhibited expected blood pharmacokinetic parameters of half-life, AUC, and volume of distribution that have been observed previously by us and others (Koumenis et al, 2000;Leong et al, 2006;Kontermann, 2009;Pepinsky et al, 2011). The pharmacokinetic parameters for the CNS compartments paralleled serum pharmacokinetic measurements except that only a small fraction of the systemically administered compounds reached the CNS.…”

Section: Downloaded Fromsupporting

confidence: 78%

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Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Pepinsky¹,

Shao²,

Ji³

et al. 2011

J Pharmacol Exp Ther

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LINGO-1 (leucine-rich repeat and Ig domain containing NOGO receptor interacting protein-1) is a negative regulator of myelination and repair of damaged axons in the central nervous system (CNS). Blocking LINGO-1 function leads to robust remyelination. The anti-LINGO-1 Li81 antibody is currently being evaluated in clinical trials for multiple sclerosis (MS) and is the first MS therapy that directly targets myelin repair. LINGO-1 is selectively expressed in brain and spinal cord but not in peripheral tissues. Perhaps the greatest concern for Li81 therapy is the limited access of the drug to the CNS. Here, we measured Li81 concentrations in brain, spinal cord, and cerebral spinal fluid in rats after systemic administration and correlated them with dose-efficacy responses in rat lysolecithin and experimental autoimmune encephalomyelitis spinal cord models of remyelination. Remyelination was dose-dependent, and levels of Li81 in spinal cord that promoted myelination correlated well with affinity measurements for the binding of Li81 to LINGO-1. Observed Li81 concentrations in the CNS of 0.1 to 0.4% of blood levels are consistent with values reported for other antibodies. To understand the features of the antibody that affect CNS penetration, we also evaluated the pharmacokinetics of Li81 Fab2, Fab, and poly(ethylene glycol)-modified Fab. The reagents all showed similar CNS exposure despite large differences in their sizes, serum half-lives, and volumes of distribution, and area under the curve (AUC) measurements in the CNS directly correlated with AUC measurements in serum. These studies demonstrate that exposure levels achieved by passive diffusion of the Li81 monoclonal antibody into the CNS are sufficient and lead to robust remyelination.

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Section: Resultssupporting

confidence: 88%

Section: Downloaded Fromsupporting

confidence: 78%

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Pepinsky¹,

Shao²,

Ji³

et al. 2011

J Pharmacol Exp Ther

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“…The relatively short half-life of the linear multi-Fab forms also warrants further investigation. Although not necessarily a disadvantage for some applications such as solid tumor penetration (18), the half-life of the linear multi-Fabs could be extended by known techniques such as conjugation with polyethylene glycol (42,63).…”

Section: Discussionmentioning

confidence: 99%

“…L3-DR5 and L4-HER2 were collected at the additional times of 30 min and 12 and 32 h. Samples were quantitated by ELISA (41), and standard curves were generated by plotting absorbance vs concentration using four-parameter logistic curve fitting. Pharmacokinetic parameters were determined by noncompartmental and compartmental analysis as described (42).…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Design, Construction, and In Vitro Analyses of Multivalent Antibodies

Miller¹,

Meng²,

et al. 2003

The Journal of Immunology

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Some Abs are more efficacious after being cross-linked to form dimers or multimers, presumably as a result of binding to and clustering more surface target to either amplify or diversify cellular signaling. To improve the therapeutic potency of these types of Abs, we designed and generated Abs that express tandem Fab repeats with the aim of mimicking cross-linked Abs. The versatile design of the system enables the creation of a series of multivalent human IgG Ab forms including tetravalent IgG1, tetravalent F(ab′)2, and linear Fab multimers with either three or four consecutively linked Fabs. The multimerized Abs target the cell surface receptors HER2, death receptor 5, and CD20, and are more efficacious than their parent mAbs in triggering antitumor cellular responses, indicating they could be useful both as reagents for study as well as novel therapeutics.

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“…PEGylation of Fab fragments has provided increased serum half-lives and efficacy for antibody therapy for a variety of applications (23)(24)(25). The availability of maleimide-PEG has allowed conjugation to antibodies through reaction with free native or engineered cysteines (12).…”

mentioning

confidence: 99%

Passive Protection against Anthrax by Using a High-Affinity Antitoxin Antibody Fragment Lacking an Fc Region

et al. 2005

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Passive immunization has been successfully employed for protection against bacterial and viral infections for over 100 years. Immunoglobulin Fc regions play a critical role in the clearance of bacterial pathogens by mediating antibody-dependent and complement-dependent cytotoxicity. Here we show that antibody fragments engineered to recognize the protective antigen component of the B. anthracis exotoxin with high affinity and conjugated to polyethylene glycol (PEG) for prolonged circulation half-life confer significant protection against inhalation anthrax despite their lack of Fc regions. The speed and lower manufacturing cost of bacterially expressed PEGylated antibody fragments could provide decisive advantages for anthrax prophylaxis. Importantly, our results suggest that PEGylated antibody fragments may represent a unique approach for mounting a rapid therapeutic response to emerging pathogen infections.

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Modulating pharmacokinetics of an anti-interleukin-8 F(ab′)2 by amine-specific PEGylation with preserved bioactivity

Cited by 49 publications

References 18 publications

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

Design, Construction, and In Vitro Analyses of Multivalent Antibodies

Passive Protection against Anthrax by Using a High-Affinity Antitoxin Antibody Fragment Lacking an Fc Region

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