A novel class of anti-IL-12p40 antibodies

Clarke, Adam W.; Poulton, Lynn D.; Wai, Hoi Yi; Walker, Stuart A.; Victor, Shanti David; Domagała, Teresa; Mraovic, Dragana; Butt, Danyal; Shewmaker, Nina; Jennings, Phil A.; Doyle, Anthony

doi:10.4161/mabs.2.5.13081

Cited by 13 publications

(4 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, we attempted to investigate the in vivo efficacy of one of the best binders, MB23, in a mouse model for skin inflammation induced by intradermal injection of human IL-23 into the ear 42 43 . In this model, repeat dosing with human IL-23 resulted in psoriasis-like thickening of the ear skin epidermis and swelling of the ear, which could be monitored in vivo by calliper measurements ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To determine the ability of affinity-matured Alphabodies to antagonize IL-23-driven inflammation in vivo , a 40-kDa linear PEGgylated form of variant MB23 (MB23-PEG) was tested in a mouse ‘ear model’ 42 43 . Local ear skin inflammation was induced by repeated intradermal administrations of human IL-23 (1 μg) every other day within a period of 15 days into the right ear pinna of 20 male C57Bl/6J mice (Harlan Laboratories, Horst, Netherlands) that were 10 weeks old at the start of the experiment.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Structural basis of IL-23 antagonism by an Alphabody protein scaffold

et al. 2014

View full text Add to dashboard Cite

Protein scaffolds can provide a promising alternative to antibodies for various biomedical and biotechnological applications, including therapeutics. Here we describe the design and development of the Alphabody, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold. We report affinity-matured Alphabodies with favourable physicochemical properties that can specifically neutralize human interleukin (IL)-23, a pivotal therapeutic target in autoimmune inflammatory diseases such as psoriasis and multiple sclerosis. The crystal structure of human IL-23 in complex with an affinity-matured Alphabody reveals how the variable interhelical groove of the scaffold uniquely targets a large epitope on the p19 subunit of IL-23 to harness fully the hydrophobic and hydrogen-bonding potential of tryptophan and tyrosine residues contributed by p19 and the Alphabody, respectively. Thus, Alphabodies are suitable for targeting protein–protein interfaces of therapeutic importance and can be tailored to interrogate desired design and binding-mode principles via efficient selection and affinity-maturation strategies.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Structural basis of IL-23 antagonism by an Alphabody protein scaffold

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Transgenic mice that overexpressed the p40 subunit or nontransgenic mice injected with recombinant IL-23 developed inflammatory skin disease, showing comparable phenotype to psoriatic patients . Inhibition of both IL-12 and IL-23 pathways by anti-p40 antibodies proved to be therapeutically beneficial in both animal models, as well as in patients . Ustekinumab, an anti-p40 antibody, was recently approved by the FDA for treating psoriasis …”

Section: Introductionmentioning

confidence: 99%

Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors

Liang¹,

Abbema²,

Balázs³

et al. 2013

J. Med. Chem.

View full text Add to dashboard Cite

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.

show abstract

“…Alternatively, the use of an inhibitor that selectively interferes with the effect of the complete IL-12p70 and IL-23 molecules but not with the inhibitory IL-12p40 subunit would be an ideal approach to improve Kasai outcome. Clarke et al [ 41 ] reported an antibody with such described activity.…”

Section: Discussionmentioning

confidence: 99%

Preoperative Serum IL-12p40 Is a Potential Predictor of Kasai Portoenterostomy Outcome in Infants with Biliary Atresia

Goda

Khedr

El-Shenawy

et al. 2017

Gastroenterology Research and Practice

View full text Add to dashboard Cite

The standard-of-care treatment for biliary atresia (BA) is surgical restoration of bile flow by Kasai portoenterostomy. We aimed to study serum interleukin- (IL-) 12p40, a natural antagonist for the proinflammatory IL-12p70, and its relation to surgical outcomes of BA. The study included 75 infants with neonatal cholestasis: BA group (n = 25), non-BA cholestasis group (n = 30), and neglected BA group (n = 20), in addition to thirty healthy neonates serving as controls. IL-12p40 was measured by ELISA in all individuals and a second assessment was performed 3 months postoperatively in the BA group. The surgical outcomes were classified as successful (bilirubin ≤ 2 mg/dl) or failed (bilirubin > 2 mg/dl). IL-12p40 was higher in BA compared to that in the non-BA and control groups (P values were 0.036 and <0.0001, resp.) but comparable to that in the neglected BA group. Preoperative IL-12p40 levels in BA patients were significantly higher in successful Kasai compared with failed Kasai and a cutoff level of 547.47 pg/ml could predict the successful outcome with 87.5% sensitivity and 82.4% specificity. Three-month postoperative IL-12p40 tended to decrease in both the successful and failed groups. In conclusion, preoperative serum IL-12p40 is a potential predictor of Kasai outcome. Serial postoperative measurements may anticipate the failure of an initially successful operation, hence the need for liver transplantation.

show abstract

A novel class of anti-IL-12p40 antibodies

Cited by 13 publications

References 25 publications

Structural basis of IL-23 antagonism by an Alphabody protein scaffold

Structural basis of IL-23 antagonism by an Alphabody protein scaffold

Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors

Preoperative Serum IL-12p40 Is a Potential Predictor of Kasai Portoenterostomy Outcome in Infants with Biliary Atresia

Contact Info

Product

Resources

About