Complex Pharmacokinetics of a Humanized Antibody Against Human Amyloid Beta Peptide, Anti-Abeta Ab2, in Nonclinical Species

Vugmeyster, Yulia; Szklut, Pam; Wensel, David; Ross, John E.; Xu, Xin; Awwad, Michel; Gill, Davinder; Tchistiakov, Lioudmila; Warner, Garvin L.

doi:10.1007/s11095-011-0405-x

Cited by 45 publications

(25 citation statements)

References 30 publications

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“…Fast clearance observed for a few antibodies has been associated with specific 14,15 or non-specific 13,16 off-target binding. During antibody generation and optimization, most of the antibodies in our panel were screened for lack of binding to closely related antigen homologs.…”

Section: Resultsmentioning

confidence: 99%

“…8 One potential mechanism that can contribute to faster than expected clearance is off-target binding. [13][14][15][16] Although highly specific off-target binding can sometimes be identified and eliminated, 14 off-target binding is often of unknown origin and difficult to saturate with an increase in dose. In vitro systems to evaluate and predict the in vivo absorption, distribution, metabolism, and mAbs Volume 4 Issue 6 in cynomolgus monkeys were collected for 52 humanized and human antibodies.…”

Section: Introductionmentioning

confidence: 99%

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A strategy for risk mitigation of antibodies with fast clearance

Hötzel¹,

Theil²,

Bernstein³

et al. 2012

mAbs

216

291

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A strategy for risk mitigation of antibodies with fast clearance

Hötzel¹,

Theil²,

Bernstein³

et al. 2012

mAbs

216

291

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“…[7][8][9][10][11] However, there are more examples of aberrant pharmacokinetic observations for bispecific mAbs that are unexplainable, and not readily attributable to these 'other' mechanisms that can influence mAb disposition. [11][12][13][14][15][16][17][18] Since these inferior in vivo properties can limit the potential advantages offered pharmacologically, further study of factors influencing their disposition is critical to their successful development for therapeutic application. In addition, despite the increased emphasis on developing these more complex structures, there remains a substantial gap in understanding the factors in vivo that result in the aberrant peripheral clearance of some bispecific antibodies.…”

Section: Introductionmentioning

confidence: 99%

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Datta‐Mannan

Croy

Schirtzinger

et al. 2016

mAbs

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(2016) Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys, mAbs, 8:5, 969-982, DOI: 10.1080/19420862.2016 To link to this article: https://doi.org/10. 1080/19420862.2016 ABSTRACT Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgGscFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.

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“…[5][6][7] There is currently a gap between the properties of small molecules and biologics. Cyclic peptides offer the potential of filling this gap and represent a class of molecules that have the specificity and potency of larger protein biologics.…”

Section: 4)mentioning

confidence: 99%

Rapid Analysis of Cyclic Peptide Cyclosporine A by HPLC Using a Column Packed with Nonporous Particles

Sakai‐Kato¹,

Nanjo²,

Goda³

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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We developed a rapid and efficient analytical technique for cyclosporine A using HPLC on a column packed with 2-µm nonporous octadecylsilyl silica particles. Under optimized conditions, cyclosporine A was separated with high resolution from other cyclic peptides within 3 min, because the mass transfer resistance in the stationary phase was reduced by the use of the small, nonporous particles. Although the plate number increased greatly with the increase in the column temperature, the retention times were not affected. This behavior is different from other cyclic peptides or linear peptides. Based on its physicochemical characteristics, cyclosporine A is a poor hydrogen bond donor, and has a small topological polar surface area, low rotatable bond count, and high log P value. These results show that cyclosporine A is structurally rigid and undergoes poor water solvation even at high temperature. In the context of the rapid development of cyclic peptides with similar physicochemical characteristics to cyclosporine A, our developed method is useful for the development of cyclic peptide therapeutics.

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Complex Pharmacokinetics of a Humanized Antibody Against Human Amyloid Beta Peptide, Anti-Abeta Ab2, in Nonclinical Species

Abstract: These data predict that elimination of Ab2 in healthy or AD humans is expected to be slow, with t(1/2) similar to that observed for other humanized antibodies.

Cited by 45 publications

References 30 publications

A strategy for risk mitigation of antibodies with fast clearance

A strategy for risk mitigation of antibodies with fast clearance

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Rapid Analysis of Cyclic Peptide Cyclosporine A by HPLC Using a Column Packed with Nonporous Particles

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