Modotuximab

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The Sym004 product is a mixture of two synergistic full-length anti-EGFR antibodies "(Modotuximab (lab code: 1024-DS) + Futuximab (lab code: 992-DS)", which bind to two separate non-overlapping epitopes on EGFR. The combination has a unique mechanism of action, which leads to sustained growth inhibition of cancer cells. Sym004 has proven to be superior to available monoclonal antibodies in several established animal models and has shown promising results in early human clinical trials. Sym004 is not only designed to block ligand binding, receptor activation and downstream signaling but also elicits effective removal of the EGFR receptors from the cancer cell surface by inducing EGFR internalization and degradation. Both Sym004 antibodies, called 992 and 1024, are mandatory in order to cross-link EGFR receptors on the cell surface, which leads to very effective receptor elimination and induction of secondary effector functions. Such extensive crosslinking of the receptors cannot be achieved with a single monoclonal antibody.

Inn NameModotuximab
Usan NameModotuximab
Lab Codes1024-DS, Sym-004, (Sym-004 = Modotuximab + Futuximab)
Chemical NameZatuximab

Immunoglobulin G1-kappa, anti-(human epidermal growth factor receptor (proto-oncogene c-ErbB-1, receptor tyrosine-protein kinase erbB-1, EC=2.7.10.1)); human mouse chimeric monoclonal antibody: γ1 heavy chain (1-448) [Mus musculus VH (IGHV1S81*02 (92%) –(IGHD)-IGHJ4*01 [8.8.12] (1-119) -Homo sapiens IGHG1*03{CH3 K107>-(449)} (120-448)] (222-219')-disulfide with kappa light chain (1'-219') [Mus musculus V-KAPPA (IGKV2-109*01-IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')] dimer (228-228'':231-231'')-bisdisulfide
Alternate NameImmunoglobulin G1-kappa, anti-[Homo sapiens EGFR (epidermal growth factor receptor, ERBB1, HER1) domain III], chimeric monoclonal antibody; gamma1 heavy chain (1-448) [Mus musculus VH (IGHV1S81*02 - (IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*03 CHS K2>del (120-448)], (222-219')-disulfide with kappa light chain (1'- 219') [Mus musculus V-KAPPA (IGKV2-109*01 -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (228-228'':231-231'')-
bisdisulfide dimer

Immunoglobulin G1, anti-(human epidermal growth factor receptor extracellular domain III) (human-Mus musculus monoclonal 1024 DS heavy chain), disulfide with human-Mus musculus monoclonal 1024 DS light chain, dimer

Chimeric IgG anti-EGFR mAb (1024)
SequenceHeavy chain
QVQLQQPGAE LVEPGGSVKL SCKASGYTFT SHWMHWVKQR PGQGLEWIGE 50
INPSSGRNNY NEKFKSKATL TVDKSSSTAY MQFSSLTSED SAVYYCVRYY 100
GYDEAMDYWG QGTSVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150
YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200
ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250
DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350
YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400
DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPG 448

Light chain
DIVMTQAAFS NPVTLGTSAS ISCRSSKSLL HSNGITYLYW YLQKPGQSPQ 50'
LLIYQMSNLA SGVPDRFSSS GSGTDFTLRI SRVEAEDVGV YYCAQNLELP 100'
YTFGGGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150'
VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200'
VTHQGLSSPV TKSFNRGEC 219'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro
22-96 22''-96'' 23'-93' 23'''-93''' 139'-199' 139'''-199''' 146-202 146''-202''
219'-222 219'''-222'' 228-228'' 231-231'' 263-323 263''-323'' 369-427 369''-427''

Glycosylation sites (N)
Asn-299 Asn-299''
Chemical StructureModotuximab.png
Molecular FormulaC6500H10022N1722O2040S48 (protein)
Cas Registry Number1310460-86-6
New Molecular EntityYes
OriginatorSymphogen A/S
Mechanism Of ActionEpidermal growth factor receptor antagonists
Who Atc CodesL01X-C (Monoclonal antibodies)
Ephmra CodesL1G (Monoclonal Antibody Antineoplastics)
IndicationSquamous Non-Small Cell Lung Cancer, Metastatic Colorectal Cancer, Malignant Glioma

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