In vitro potency, pharmacokinetic profiles and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus

Vugmeyster, Yulia; Guay, Heath; Szklut, Pamela; Qian, Ming; Jin, Macy; Widom, Angela; Spaulding, Vikki; Bennett, Frann; Lowe, Leslie; Andreyeva, Tatyana; Lowe, David C.; Lane, Steven; Thom, George; Valge-Archer, Viia; Gill, Davinder; Young, Deborah; Bloom, Laird

doi:10.4161/mabs.2.3.11850

Cited by 42 publications

(43 citation statements)

References 32 publications

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“…Neutralization of the IL-21 pathway reduced basal IgG and autoantibody titers, and reduced the severity and incidence of skin lesions, lymphadenopathy and splenomegaly in MRL-Fas lpr mice. Blockade of the IL-21 pathway also prevented the development of nephritis in MRL-Fas lpr mice as determined by reduced urine protein, and demonstrated reduced glomerular basement membrane thickening, glomerular Ig deposition, and immune cell infiltration upon histopathologic analysis [78,79].…”

Section: Preclinical Evidence For a Role Of Il-21 In The Pathogenesismentioning

confidence: 99%

Role of IL-21 in Systemic Lupus Erythematosus

Jung¹,

Guay²

2011

J Clin Cell Immunol

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Systemic lupus erythematosus is a chronic autoimmune disease that affects multiple organ systems and tissues. Activation and differentiation of autoreactive T and B cells, and the formation of pathogenic autoantibodies are central to disease pathogenesis. IL-21 is the most recently identified member of the family of cytokines whose receptors share the common γ c . IL-21 is a pleotropic cytokine that regulates the activation, differentiation and expansion of B and T cells. Here, we review the role of IL-21 in T and B cell biology, and provide insight into the potential role of IL-21 in the development of SLE.

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Section: Preclinical Evidence For a Role Of Il-21 In The Pathogenesismentioning

confidence: 99%

Role of IL-21 in Systemic Lupus Erythematosus

Jung¹,

Guay²

2011

J Clin Cell Immunol

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“…48 Indeed, blocking IL-21 activity has been shown to reduce disease symptoms in a variety of animal disease and xenograft models (ref. [49][50][51][52][53][54][55][56] and our unpublished results).…”

Section: Introductionmentioning

confidence: 99%

“…Other groups have demonstrated antidisease activity in mouse models using a homodimeric soluble mouse IL-21R-Fc reagent. 49,51,[59][60][61][62][63][64] Given that all of our neutralizing mAbs consistently neutralize IL-21 activity at least as potently as the heterodimeric human IL-21R/γ c -Fc, and by inference far more potently than the human homodimeric IL-21R-Fc, it appears likely that an anti-IL-21 mAb will also be able to suppress IL-21-mediated autoimmunity and inflammation in vivo. We have also confirmed using high affinity rat anti-mIL-21 or mouse anti-mIL-21 mAbs that neutralizing mIL-21 in vivo in mouse models of colitis/psoriasis and arthritis can elicit therapeutic benefit (unpublished results).…”

Section: Introductionmentioning

confidence: 99%

“…Several different mechanistic strategies could be considered to interfere with IL-21 mediated cell signaling: antagonists directed against (or composed of) the IL-21R, 49,50 antagonists directed against the common cytokine receptor γ chain (γ c ) (though these would impact other members of this cytokine family), or antagonists directed against IL-21 itself. 51,52 We describe here the isolation and characterization of neutralizing monoclonal antibodies (mAbs) directly targeting IL-21 and interfering with its binding to IL-21R or the IL-21R/γ c heterodimer.…”

Section: Introductionmentioning

confidence: 99%

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Generation and characterization of human anti-human IL-21 neutralizing monoclonal antibodies

Maurer¹,

Garrigues

Jaspers

et al. 2012

mAbs

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“…An example of the interdependency between PK, PD, and immunogenicity profiles, as well as inverse dose response for induction of ADAs, is described for the neutralizing anti-IL-21R antibodies that are being investigated for the treatment of autoimmune conditions (7). The pharmacological activities and PK profiles of two different human anti-IL-21R antibodies (referred to as Ab-01 and Ab-02) that differ in their in vitro potency and PK were examined in the MRLFas lpr mouse model of lupus.…”

Section: Case Study 1: Anti-il-21r Absmentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion (ADME) Studies of Biotherapeutics for Autoimmune and Inflammatory Conditions

Vugmeyster

Harrold

2012

AAPS J

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Abstract. Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of biotherapeutics is crucial for clinical, as well as commercial, success of these drugs. This review focuses on the common questions and challenges in ADME optimization of biotherapeutics for inflammatory conditions. For these immunomodulatory and/or immunosuppressive biotherapeutics, special consideration should be given to the assessment of the interdependency of ADME profiles, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and immunogenicity profiles across various preclinical species and humans, including the interdependencies both in biology and in assay readouts. The context of usage, such as dosing regimens, extent of disease, concomitant medications, and drug product characteristics may have a direct or indirect (via modulation of immunogenicity) impact on ADME profiles of biotherapeutics. Along these lines, emerging topics include assessments of preexisting reactivity to a biotherapeutic agent, impact of immunogenicity on tissue exposure, and analysis of penetration to normal versus inflamed tissues. Because of the above complexities and interdependences, it is essential to interpret PK, PD, and anti-drug antibody results in an integrated manner. In addition, because of the competitive landscape in autoimmune and inflammatory markets, many pioneering ADME-centric protein engineering and subsequent in vivo testing (such as optimization of novel modalities to extend serum and tissue exposures and to improve bioavailability) are being conducted with biotherapeutics in this therapeutic area. However, the ultimate challenge is demonstration of the clinical relevance (or lack thereof) of modified ADME and immunogenicity profiles.

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In vitro potency, pharmacokinetic profiles and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus

Cited by 42 publications

References 32 publications

Role of IL-21 in Systemic Lupus Erythematosus

Role of IL-21 in Systemic Lupus Erythematosus

Generation and characterization of human anti-human IL-21 neutralizing monoclonal antibodies

Absorption, Distribution, Metabolism, and Excretion (ADME) Studies of Biotherapeutics for Autoimmune and Inflammatory Conditions

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