Trastuzumab duocarmazine

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NCI: An antibody-drug conjugate (ADC) composed of the recombinant humanized anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab linked, via a cleavable linker, to the duocarmycin prodrug, seco-duocarmycin-hydroxybenzamide-azaindole (seco-DUBA), with potential antineoplastic activity. Upon administration of trastuzumab vc-seco-DUBA, the trastuzumab moiety binds to HER2 on the tumor cell surface, which triggers the endocytosis of this agent. The linker is then cleaved inside the tumor cell by proteases at the dipeptide valine-citrulline (vc), and releases the active moiety, duocarmycin. Duocarmycin binds to the minor groove of DNA, alkylates adenine at the N3 position, and induces cell death. In addition, trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells that overexpress HER2. HER2 is overexpressed by many carcinomas and is associated with a poor prognosis.

Inn NameTrastuzumab duocarmazine
Lab CodesSYD-985, Trastuzumab vc-seco-DUBA
Chemical NameImmunoglobulin G1-kappa, anti-[Homo sapiens ERBB2 (epidermal growth factor receptor 2, receptor tyrosineprotein kinase erbB-2, EGFR2, HER2, HER-2, p185cerbB2, NEU, CD340)], humanized monoclonal antibody conjugated to the pro-drug seco-duocarmycinhydroxybenzamide-azaindole (seco-DUBA); gamma1 heavy chain (1-449) [humanized VH (Homo sapiens (IGHV3-66-*01 (81.60%) -(IGHD)-IGHJ6*01) [8.8.13] (1-120) -Homo sapiens IGHG1*01, G1m17, nG1m1 (CH1 (121-218), hinge (219-233),CH2 (234-343), CH3 D12>E (359), L14>M (361) (344-448), CHS K>del (449)) (121-449)], (223-214')-disulfide with kappa light chain (1’-214’) [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (86.30%) -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01, Km3 (108'-214')]; dimer (229-229":232-232")-bisdisulfide, conjugated on an average of 2 or 4 cysteines, to seco-DUBA via the cleavable linker N-[2-(2-maleimidoethoxy)ethoxycarbonyl]-L-valyl-L-citrullinylp- aminobenzyloxycarbonyl-N-[2-(2-hydroxyethoxy)ethyl]-N-[2-(methylamino)ethyl]carbamoyl
Alternate NameADC SYD985
antibody-drug conjugate SYD985
trastuzumab-drug conjugate SYD985
SequenceHeavy chain
EVQLVESGGG LVQPGGSLRL SCAASGFNIK DTYIHWVRQA PGKGLEWVAR 50
IYPTNGYTRY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCSRWG 100
GDGFYAMDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200
YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG 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 ITCRASQDVN TAVAWYQQKP GKAPKLLIYS 50
ASFLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQQ HYTTPPTFGQ 100
GTKVEIKRTV 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''
*Two or three of the inter-chain disulfide bridges are not present, on average 2 or 4 cysteinyl being
conjugated each via a thioether bond to a drug linker.

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación
H CH2 N84.4:
300, 300''
Fucosylated complex bi-antennary CHO-type glycans
Potential modified residues
Chemical StructureTrastuzumab duocarmazine.png
Cas Registry Number1642152-40-6
OriginatorSynthon
Mechanism Of ActionAlkylating agent
Who Atc CodesL01D (Cytotoxic Antibiotics and Related Substances)
L01X-C03 (Trastuzumab)
Ephmra CodesL1D (Antineoplastic Antibiotics)
L1G (Monoclonal Antibody Antineoplastics)
IndicationSolid Tumors

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