Risankizumab

Risankizumab also known as BI-655066 is a humanized monoclonal antibody targeting interleukin 23A (IL-23A). Risankizumab is part of a collaboration between Boehringer Ingelheim and AbbVie. The therapeutic potential of risankizumab is being evaluated in immunological disorders, including Crohn's disease, psoriasis, psoriatic arthritis, and asthma. It is currently in phase II clinical drug trials for Crohn's disease, psoriatic arthritis, and asthma; it is in phase III clinical drug trials for psoriasis.

Clinical Drug Trial Information

May 24, 2016 - Crohn's Disease

Through phase II clinical drug trials Risankizumab was shown to be more effective in terms of significantly reducing symptoms than placebo condition in patients with moderately-to-severely active Crohn’s disease. After 12 weeks, 24% and 37% of patients achieved clinical remission (little to no symptoms) with treatment of either 200 mg (41 test subjects) and 600 mg (41 test subjects) risankizumab, respectively, compared with 15% (39 test subjects) of patients receiving placebo. Endoscopic remission (normalization of the lining of bowel as seen during an endoscopy) was achieved by 15% (41 test subjects) and 20% (41 test subjects) of patients receiving 200 mg and 600 mg risankizumab, respectively, compared with three percent of patients receiving placebo. Risankizumab was administered intravenously during weeks zero, four, and eight.[1]

March 11, 2015 - Psoriasis

In phase II clinical drug trials, thirty-nine patients received single-dose Risankizumab, 18 of which received the drug intravenously, 13 subcutaneously, and 8 received the placebo drug. There were several instances that adverse effects occurred but in the same frequency for the placebo and the experimental groups. Four considerably serious adverse events occurred, but it was determined that they were not treatment related, in the Risankizumab treated patients. Risankizumab was associated with clinical improvement in individuals treated with the drug, from week 2 and maintained for up to 66 weeks after treatment. At week 12 of treatment, 75%, 90%, and 100% decreases in the psoriasis area and Severity Index were achieved by 87%, 58%, and 16% of Risankizumab treated patients, regardless of dose, respectively, versus individuals receiving placebo. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10(-6)). The conclusion of this clinical drug trial was that Risankizumab was very well tolerated and associated with quick, significant, and long-lasting clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.[2]

Mechanism of Action and Pharmacodynamic Effects

The IL23/IL17 axis plays an important role in the development of chronic inflammation, with potential genetic links between the IL23 receptor (IL23R) or its ligand identified in inflammatory diseases such as psoriasis, inflammatory bowel disease, and graft-versus-host disease. Signaling through the IL23R induces Janus kinase 2 (JAK2) and tyrosine kinase 2 (tyk2) phosphorylation and leads to increased levels of the inflammatory cytokines IL17 and IL22. Risankizumab binds to the p19 sub-unit of IL23, IL23A, preventing receptor activation and thereby disrupting the IL23/IL17 axis.[3]

Structural Details

Below is a detailed structural make-up of Risankizumab (Singh et al.):[4]

Heavy chain
QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DQTIHWMRQA PGQGLEWIGY 50
IYPRDDSPKY NENFKGKVTI TADKSTSTAY MELSSLRSED TAVYYCAIPD 100
RSGYAWFIYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200
YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGG PSVFLFPPKP 250
KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350
VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400
LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG 449

Light chain
DIQMTQSPSS LSASVGDRVT ITCKASRDVA IAVAWYQQKP GKVPKLLIYW 50
ASTRHTGVPS RFSGSGSRTD FTLTISSLQP EDVADYFCHQ YSSYPFTFGS 100
GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200
LSSPVTKSFN RGEC 214

Disulfide bridges location
Intra-H (C23-C104) 22-96 147-203 264-324 370-428
22-96 147-203 264-324 370-428
Intra-L (C23-C104) 23'-88' 134'-194'23-88 134-194
Inter-H-L (h 5-CL 126) 223-214' 223-214'
Inter-H-H (h 11, h 14) 229-229 232-232

N-glycosylation sites H CH2 N84.4:300, 300

Fucosylated complex bi-antennary CHO-type glycans[5]

References

  1. ↑ Feagan, B; et al. (May 24, 2016). "Efficacy and Safety of Induction Therapy with Selective IL-23 Inhibitor Risankizumab in Patients with Moderate-to-severe Crohn's Disease: Results of a randomized, double-blind, placebo-controlled Phase II study". Clinical Science Late-Breaking Abstract Plenary.
  2. ↑ Krueger, J; et al. (July 2015). "Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial.". J Allergy Clin Immunol. 136 (1): 116–127. doi:10.1016/j.jaci.2015.01.018.
  3. ↑ Gaffen, S.; et al. (September 2014). "The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing". Nat Rev Immonol. 9 (14): 585–600. doi:10.1038/nri3707.
  4. ↑ Singh S, Kroe-Barrett RR, Canada KA, Zhu X, Sepulveda E , Wu H, He Y, Raymond EL, Ahlberg J, Frego LE , Amodeoa LM, Catron KM, Presky, DH and Hanke JH (2015) Selective targeting of the IL23 pathway: Generation and characterization of a novel high-affinity humanized anti-IL23A antibody. mABs http://dx.doi.org/10.1080/19420862.2015.1032491
  5. ↑ "Risankizumab". Drug Spider. Retrieved May 26, 2016

[1]

  1. ↑ "Risankizumab". Drug Spider. Retrieved May 26, 2016.
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