Whole-Molecule Antibody Engineering: Generation of a High-Affinity Anti-IL-6 Antibody with Extended Pharmacokinetics

Finch, Donna K.; Sleeman, Matthew A.; Moisan, Jacques; Ferraro, Franco; Botterell, Sara; Campbell, Jamie I. D.; Cochrane, D; Cruwys, Simon; England, Elizabeth; Lane, Steven; Rendall, Elizabeth; Sinha, Monisha; Walker, Craig M.; Rees, Gareth; Bowen, Michael A.; Schneider, Amy; Liang, Meina; Faggioni, Raffaella; Fung, Michael; Mallinder, Philip R.; Wilkinson, Trevor; Kolbeck, Roland; Vaughan, Tristan J.; Lowe, David C.

doi:10.1016/j.jmb.2011.06.031

Cited by 44 publications

(32 citation statements)

References 38 publications

(41 reference statements)

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“…We then created MEDI5117 by incorporating three amino acid substitutions, M252Y, S254T, and T256E (YTE), into the Fc region of CAT-6001 to increase the antibody's half life in vivo. Pharmacokinetic studies in cynomolgus monkeys showed that the half-life of MEDI5117 was extended by 3-fold (28.4 vs. 8.4 days) and clearance was reduced by 4-fold (3.02 vs. 12.1 mL/kg/day) when compared with CAT-6001 (16,17). The half-life of MEDI5117 in humans was 84 days, significantly longer than other anti-IL6 antibodies, such as siltuximab whose half-life was 17.8 days.…”

Section: Il6 Is a Potent Growth Factor And Its Downstream Signaling Imentioning

confidence: 99%

“…MEDI5117 is a human monoclonal antibody (mAb) that potently binds and neutralizes human IL6. It was engineered to have increased persistence in circulation compared with unmodified antibodies through incorporation of YTE mutations in the Fc region (16,17). MEDI5117 inhibited IL6 signaling and suppressed the growth of lung, breast, and ovarian tumor cells in vitro and in vivo with higher potency than siltuximab.…”

Section: Introductionmentioning

confidence: 99%

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A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

Zhong¹,

Davis²,

Ouzounova

et al. 2016

Cancer Research

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Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2

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Section: Il6 Is a Potent Growth Factor And Its Downstream Signaling Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

Zhong¹,

Davis²,

Ouzounova

et al. 2016

Cancer Research

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“…This IL-6 inhibitor was generated by means of variable domain engineering to achieve sub-picomolar affinity for IL-6 and with Fc engineering to enhance its pharmacokinetic half-life [179]. A phase I trial of IV injection of MEDI5117 (30 mg, 100 mg, 300 mg or 600 mg) for RA is in progress.…”

Section: Development Of Subcutaneous Administration For Tocilizumab Amentioning

confidence: 99%

Targeting of Interleukin-6 for the Treatment of Rheumatoid Arthritis: A Review and Update

Ogata¹

2014

Rheumatology (Sunnyvale)

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Tanaka et al., Rheumatol Curr Res 2013, S4 http://dx.doi.org/10.4172/2161-1149 Review ArticleOpen Access AbstractRheumatoid Arthritis (RA) is a chronic inflammatory disease, characterized by persistent joint inflammation, systemic inflammation and immunological abnormalities. Since IL-6 plays a major role in the development of these characteristics, its targeting could reasonably be expected to constitute a novel therapeutic strategy for the treatment of RA. Tocilizumab, a humanized anti-human IL-6 receptor monoclonal antibody, has demonstrated its outstanding clinical efficacy and tolerable safety profile in phase III clinical trials for RA patients, resulting in its worldwide approval for moderate-to-severe active RA. Post-marketing clinical trials have confirmed its efficacy. This success led to the development of various other IL-6 inhibitors. Further clinical studies including head-to-head comparative studies, and clarification of the mechanisms through which tocilizumab exerts its clinical effects can be expected to identify RA patients who should be treated with tocilizumab as a first-line biologic. In addition, recent case reports and pilot studies indicate that therapies targeting IL-6 will be widely applicable to the treatment of various intractable immune-mediated diseases.

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“…IgG-FcRn interactions are pH-dependent, characterized by high-affinity binding at pH 5.5 in the endosome to promote recycling by protecting mAbs from catabolism, followed by extracellular release at pH 7.4 as a result of reduced affinity. Numerous examples have been described in which IgG Fc-region amino acid substitutions enhance pH-dependent FcRn binding, leading to improved PK properties in preclinical species (Dall'Acqua et al, 2002Hinton et al, 2004;Zalevsky et al, 2010;Finch et al, 2011) or humans (Robbie et al, 2013). An effort combining pH-dependent antigen affinity optimization with enhanced FcRn binding has been reported for tocilizumab (Igawa et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Anti-PCSK9 Antibody Pharmacokinetics and Low-Density Lipoprotein-Cholesterol Pharmacodynamics in Nonhuman Primates Are Antigen Affinity–Dependent and Exhibit Limited Sensitivity to Neonatal Fc Receptor–Binding Enhancement

Henne

Ason

Howard

et al. 2015

J Pharmacol Exp Ther

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive therapeutic target for cardiovascular disease. Monoclonal antibodies (mAbs) that bind PCSK9 and prevent PCSK9:low-density lipoprotein receptor complex formation reduce serum low-density lipoprotein-cholesterol (LDL-C) in vivo. PCSK9-mediated lysosomal degradation of bound mAb, however, dramatically reduces mAb exposure and limits duration of effect. Administration of high-affinity mAb1:PCSK9 complex (1:2) to mice resulted in significantly lower mAb1 exposure compared with mAb1 dosed alone in normal mice or in PCSK9 knockout mice lacking antigen. To identify mAb-binding characteristics that minimize lysosomal disposition, the pharmacokinetic behavior of four mAbs representing a diverse range of PCSK9-binding affinities at neutral (serum) and acidic (endosomal) pH was evaluated in cynomolgus monkeys. Results revealed an inverse correlation between affinity and both mAb exposure and duration of LDL-C lowering. Highaffinity mAb1 exhibited the lowest exposure and shortest duration of action (6 days), whereas mAb2 displayed prolonged exposure and LDL-C reduction (51 days) as a consequence of lower affinity and pH-sensitive PCSK9 binding. mAbs with shorter endosomal PCSK9:mAb complex dissociation half-lives (,20 seconds) produced optimal exposure-response profiles. Interestingly, incorporation of previously reported Fc-region amino acid substitutions or novel loop-insertion peptides that enhance in vitro neonatal Fc receptor binding, led to only modest pharmacokinetic improvements for mAbs with pH-dependent PCSK9 binding, with only limited augmentation of pharmacodynamic activity relative to native mAbs. A pivotal role for PCSK9 in mAb clearance was demonstrated, more broadly suggesting that therapeutic mAb-binding characteristics require optimization based on target pharmacology.

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Whole-Molecule Antibody Engineering: Generation of a High-Affinity Anti-IL-6 Antibody with Extended Pharmacokinetics

Cited by 44 publications

References 38 publications

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

Targeting of Interleukin-6 for the Treatment of Rheumatoid Arthritis: A Review and Update

Anti-PCSK9 Antibody Pharmacokinetics and Low-Density Lipoprotein-Cholesterol Pharmacodynamics in Nonhuman Primates Are Antigen Affinity–Dependent and Exhibit Limited Sensitivity to Neonatal Fc Receptor–Binding Enhancement

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