OP0043 Twenty-Four Weeks of Treatment with a Novel Anti-IL-6 Receptor Nanobody® (ALX-0061) Resulted in 84% ACR20 Improvement and 58% DAS28 Remission in a Phase I/Ii Study in RA

Holz, Josefin-Beate; Sargentini-Maier, L.; Bruyn, Steven De; Gachályi, B; Udvaros, Istvan; Rojkovich, Bernadette; Bruk, S.; Šrámek, P.; Korkosz, Mariusz; Krause, Karoline; Schoen, Pieter; D’Artois, J.; Verschueren, Katrien; Willems, Wouter F.; Swert, Kathleen De; Arold, Gerhard

doi:10.1136/annrheumdis-2013-eular.248

Cited by 23 publications

(15 citation statements)

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“…Affinity of ALX-0061 to sIL-6R is 2400-fold (K D = 0.19 vs. 462 pM) and to mIL-6R is 17-fold (K D = 9.1 vs. 154 pM) greater than TCZ. On the top of its better pharmacokinetic profile, Phase II clinical study confirmed the great treatment outcomes with ALX-0061 compared to placebo group demonstrated by ACR20 improvement (85 vs. 62.5 %) and DAS28 remission (45 vs. 12.5 %) (Holz et al 2013). …”

Section: Investigational Il-6 Inhibitorsmentioning

confidence: 80%

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

et al. 2015

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

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Section: Investigational Il-6 Inhibitorsmentioning

confidence: 80%

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

et al. 2015

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“…One major asset of the Nanobody technology is the flexibility to choose a format that reflects the specific kinetic needs: for chronic disease indications, where prolonged exposure is crucial, a half-life extended construct can be generated, while in acute indications non-half-life extended formats might show preferential kinetics. This advantage is demonstrated by the multiple Nanobodies including examples of both formats that are currently in clinical development in a wide array of therapeutic areas, including inflammation, infectious diseases, and hematology [3,[44][45][46].…”

Section: Resultsmentioning

confidence: 99%

Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies®

et al. 2015

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Nanobodies are antigen-binding, single variable domain proteins derived from naturally-occurring, heavy chain only antibodies. They are highly soluble, stable, and can be linked to build multi-specific formats. Several Nanobodies are currently in clinical development in different therapeutic areas, for both chronic and acute applications. For the former, prolonged exposure is achieved by half-life extending moieties that target endogenous albumin, while for the latter, non-half-life extended constructs are preferable. To demonstrate the general pharmacokinetic behavior of both formats, serum levels of seven intravenously administered Nanobodies were analyzed in cynomolgus monkeys, mice or rabbits. In monkeys, the total clearance of a monomeric irrelevant Nanobody was rapid (2.0 mL/(min*kg)) and approximated the species glomerular filtration rate, indirectly suggesting that the Nanobody was mainly eliminated via the kidneys. When linked to an anti-albumin Nanobody, a 376-fold decrease in clearance was observed, resulting in a terminal half-life of 4.9 days, corresponding to the expected species albumin half-life. Similar conclusions were drawn for (non-) half-life extended mono-, bi-and trimeric Nanobodies in mice or rabbits, suggesting that these kinetic principles apply across species. Applying this knowledge to species translation and study design is crucial for successful pre-clinical development of novel therapeutic Nanobody candidates.

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“…In the liver, these complexes could potentially bind to DR5 receptors and induce apoptosis in normal hepatocytes, with resultant hepatotoxicity. Notably, no hepatotoxicity and minimal immunogenicity has been reported with bivalent and trivalent Nanobodies ® that have been investigated in non-oncology diseases or healthy volunteers [29][30][31][32]. Interestingly, Holland and colleagues investigated the effect of HAVH autoantibodies on an anti-TNFR1 VH domain antibody (GSK1995057) in healthy human subjects [19].…”

Section: Discussionmentioning

confidence: 98%

Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor

Papadopoulos

Isaacs

Bilic

et al. 2015

Cancer Chemother Pharmacol

123

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TAS266 was associated with unexpected, significant but reversible hepatotoxicity. Although the underlying mechanism is not fully elucidated, factors including the molecule's high potency, immunogenicity to TAS266, and possibly increased DR5 expression on hepatocytes further enhancing the activity of the Nanobody(®) may have contributed to enhanced DR5 clustering and activation of hepatocyte apoptosis.

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OP0043 Twenty-Four Weeks of Treatment with a Novel Anti-IL-6 Receptor Nanobody® (ALX-0061) Resulted in 84% ACR20 Improvement and 58% DAS28 Remission in a Phase I/Ii Study in RA

Cited by 23 publications

References 0 publications

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies®

Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor

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