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Monday, 28 September 2009

New Drug Approvals - Pt. XVIII - Ustekinumab (Stelara)

Recently approved by the FDA, on September 25th 2009, was Ustekinumab, marketed under the trade name Stelara. Ustekinumab, previously known as CNTO-1275, is a first-in-class injectable biological drug blocking signalling of two distinct interleukins (IL-12 and IL-23) and is indicated for the treatment of adults with moderate to severe plaque psoriasis. Psoriasis (ICD-10: L40) is a complex autoimmune disease, typically leading to the formation of scaly red or silvery-white plaques on the skin. Another drug with the same mechanism as Ustekinumab (blocking IL-12 and IL-23 signalling) is ABT-874, ABT-874 is currently still in clinical trials.
Ustekinumab is dosed as a subcutaneous injection given at weeks 0 and 4, followed subsequently by every-12-week maintenance dosing. The recommended starting dose of is 45 mg for patients weighing 100 kg or less, and 90 mg for patients weighing more than 110 kg (the 45mg dose corresponds to a 0.31 umol dose).
Ustekinumab is is a human IgG1қ monoclonal antibody and is the first drug to target IL-12 and IL-23 cytokines, these are two naturally occurring secreted, heterodimeric proteins (two distinct proteins (themselves derived from two distinct genes) bound in a specific complex), they are involved in inflammatory and immune responses, such as the activation of CD4+ and Natural Killer T-cells. Ustekinumab binds with high affinity and specificity to the p40 protein shared as a common subunit by both IL-12 and IL-23. Through targeting the shared p40 component, Ustekinumab is able to block signalling by both interleukins. IL-12 and IL-23 eventually signal via master inflammatory system regulators tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB).
<CHEMBL_DRUG>
<DRUG_NAME="Ustekinumab" TRADEMARK_NAME="Stelara" RESEARCH_CODE="CNTO1275" APPROVAL_DATE="25-SEPT-2009" DRUG_MOLECULAR_WEIGHT="145650">
<DRUG_SUBUNIT="Heavy gamma-1 chain">
EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWLGWVRQMPGKGLDWIGI
MSPVDSDIRYSPSFQGQVTMSVDKSITTAYLQWNSLKASDTAMYYCARRR
PGQGYFDFWGQGTLVTVSSSSTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
</DRUG_SUBUNIT>
<DRUG_SUBUNIT NAME="Light kappa chain">
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPYTFGQ
GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG
LSSPVTKSFNRGEC
</DRUG_SUBUNIT>
<DRUG_TARGET UNIPROT="P29460" TARGET_NAME="p40 subunit of IL-12 and IL-23">
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSG
KTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKE
PKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGA
ATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYEN
YTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLT
FCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEW
ASVPCS
</DRUG_TARGET>
</DRUG>
</CHEMBL_DRUG>
The license holder for Ustekinumab is Johnson & Johnson. and the product website is www.stelarainfo.com.

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