Cixutumumab

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Cixutumumab (IMC-A12) is a human monoclonal antibody for the treatment of solid tumors.^[1]^[2]

This drug was developed by ImClone Systems, since acquired by Eli Lilly, using phage display technology from Dyax.^{[citation needed]}

It is a fully human IgG1 monoclonal antibody directed against the human insulin-like growth factor-1 receptor (IGF-1R) with potential antineoplastic activity. Cixutumumab selectively binds to membrane-bound IGF-1R, thereby preventing the binding of the ligand IGF-1 and subsequent activation of PI3K/AKT signaling pathway. Downregulation of the PI3K/AKT survival pathway may result in the induction of cancer cell apoptosis and may decrease cancer cellular proliferation. IGF-1R, a receptor tyrosine kinase of the insulin receptor superfamily overexpressed by many cancer cell types, stimulates cell proliferation, enables oncogenic transformation, and suppresses apoptosis; IGF-1R signaling has been implicated in tumorigenesis and metastasis.^[3]

Research

Phase II clinical trials have been completed in patients with non-small cell lung cancer,^[4]^[5]^[6] metastatic rhabdomyosarcoma,^[7] metastatic prostate cancer,^[8] metastatic pancreatic cancer,^[9] metastatic esophageal cancer,^[10] bone cancer,^[11] sarcoma,^[12] solid tumors,^[13] ocular melanoma,^[14] hepatocellular carcinoma,^[15]^[16] breast cancer^[17] and other forms of cancer. Despite these extensive trials, more than 45 phase I and II clinical trials in total, phase III trials have never been undertaken and Eli Lilly has removed cixutumumab from their development pipeline.^[18]

References

^ "Statement On A Nonproprietary Name Adopted – Cixutumumab" (PDF). The USAN Council. American Medical Association.
^ McKian KP, Haluska P (July 2009). "Cixutumumab". Expert Opinion on Investigational Drugs. 18 (7): 1025–33. doi:10.1517/13543780903055049. PMC 2939377. PMID 19548856.
^ "Cixutumumab". National Cancer Institute. 2011-02-02.
^ Clinical trial number NCT01263782 for "BATTLE-FL: Front-Line Biomarker-Integrated Treatment Study in Non Small Cell Lung Cancer" at ClinicalTrials.gov
^ Clinical trial number NCT00955305 for "Paclitaxel, Carboplatin, and Bevacizumab With or Without Cixutumumab in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer" at ClinicalTrials.gov
^ Clinical trial number NCT00986674 for "Carboplatin and Paclitaxel Combined With Cetuximab and/or IMC-A12 in Patients With Advanced Non-Small Cell Lung Cancer" at ClinicalTrials.gov
^ Clinical trial number NCT01055314 for "Temozolomide, Cixutumumab, and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma" at ClinicalTrials.gov
^ Clinical trial number NCT01120236 for "Bicalutamide and Goserelin or Leuprolide Acetate With or Without Cixutumumab in Treating Patients With Newly Diagnosed Metastatic Prostate Cancer" at ClinicalTrials.gov
^ Clinical trial number NCT00617708 for "S0727 Gemcitabine Hydrochloride and Erlotinib Hydrochloride With or Without Monoclonal Antibody Therapy in Treating Patients With Metastatic Pancreatic Cancer That Cannot Be Removed By Surgery" at ClinicalTrials.gov
^ Clinical trial number NCT01142388 for "Paclitaxel With or Without Cixutumumab as Second-Line Therapy in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer" at ClinicalTrials.gov
^ Clinical trial number NCT01016015 for "Temsirolimus and Cixutumumab in Treating Patients With Locally Advanced, Metastatic, or Recurrent Soft Tissue Sarcoma or Bone Sarcoma" at ClinicalTrials.gov
^ Clinical trial number NCT01614795 for "Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma" at ClinicalTrials.gov
^ Clinical trial number NCT00831844 for "Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors" at ClinicalTrials.gov
^ Clinical trial number NCT01413191 for "Cixutumumab in Treating Patients With Metastatic Melanoma of the Eye" at ClinicalTrials.gov
^ Clinical trial number NCT00906373 for "A Study of IMC-A12 in Combination With Sorafenib in Patients With Advanced Cancer of the Liver" at ClinicalTrials.gov
^ Clinical trial number NCT00639509 for "IMC-A12 in Treating Patients With Advanced Liver Cancer" at ClinicalTrials.gov
^ Clinical trial number NCT00728949 for "A Study for Safety and Effectiveness of IMC-A12 by Itself or Combined With Antiestrogens to Treat Breast Cancer" at ClinicalTrials.gov
^ "Clinical Development Pipeline". Eli Lilly and Company. Archived from the original on 13 January 2017.

Monoclonal antibodies for tumors

Tumor

Human	Adecatumumab^§ Amivantamab Ascrinvacumab^§ Atezolizumab Balstilimab^† Botensilimab Cixutumumab^§ Conatumumab^§ Daratumumab Drozitumab^§ Duligotumab^§ Dusigitumab^§ Enfortumab vedotin Enoticumab^§ Figitumumab^§ Flanvotumab^§ Ganitumab^† Glembatumumab vedotin^† Intetumumab^§ Ipilimumab Iratumumab^§ Istiratumab Icrucumab^§ Lexatumumab^§ Lucatumumab^§ Mapatumumab^§ Narnatumab^§ Necitumumab Nesvacumab^§ Nivolumab^# Ofatumumab Olaratumab^† Panitumumab Patritumab^§ Pembrolizumab^# Pritumumab^§ Radretumab^§ Ramucirumab Rilotumumab^† Robatumumab^§ Seribantumab^§ Tarextumab^§ Tisotumab vedotin Teprotumumab^† Tovetumab^§ Vantictumab^§ Votumumab^§ Zalutumumab^†
Mouse	Abagovomab Altumomab pentetate Anatumomab mafenatox Arcitumomab Bectumomab Blinatumomab Capromab pendetide Detumomab Edrecolomab Ibritumomab tiuxetan Igovomab Lilotomab Minretumomab Mitumomab Nacolomab tafenatox Moxetumomab pasudotox Naptumomab estafenatox Oregovomab Pemtumomab^† Racotumomab Satumomab pendetide Solitomab Taplitumomab paptox Nofetumomab merpentan Pintumomab Tenatumomab Tositumomab
Chimeric	Amatuximab^§ Bavituximab^§ Brentuximab vedotin Carotuximab^† Cetuximab Derlotuximab biotin^§ Dinutuximab Ecromeximab^§ Ensituximab^§ Futuximab^§ Girentuximab^† Indatuximab ravtansine^§ Isatuximab Loncastuximab tesirine Margetuximab Mirvetuximab soravtansine Rituximab^# Siltuximab Ublituximab Zolbetuximab
Humanized	Abituzumab^§ Alemtuzumab Belantamab mafodotin Bevacizumab Bivatuzumab mertansine^§ Brontictuzumab^§ Cantuzumab mertansine^§ Cantuzumab ravtansine^§ Cirmtuzumab Citatuzumab bogatox^§ Clivatuzumab tetraxetan Cofetuzumab pelidotin Dacetuzumab^§ Demcizumab^§ Dalotuzumab^§ Denintuzumab mafodotin^§ Elotuzumab Emactuzumab Emibetuzumab^§ Enoblituzumab^§ Epcoritamab Etaracizumab^§ Farletuzumab^§ Ficlatuzumab^§ Flotetuzumab^§ Gemtuzumab ozogamicin Glofitamab Imgatuzumab^§ Inotuzumab ozogamicin Labetuzumab^§ Lifastuzumab vedotin^§ Lintuzumab^§ Lorvotuzumab mertansine^§ Lumretuzumab^§ Matuzumab^§ Milatuzumab^§ Naxitamab Nimotuzumab^† Obinutuzumab Ocaratuzumab^§ Otlertuzumab^§ Onartuzumab^§ Oportuzumab monatox^† Parsatuzumab^§ Pertuzumab Pinatuzumab vedotin^§ Polatuzumab vedotin Rosmantuzumab Rovalpituzumab tesirine^† Sacituzumab govitecan Sibrotuzumab^§ Simtuzumab^§ Sofituzumab vedotin^§ Tacatuzumab tetraxetan^§ Tigatuzumab^§ Trastuzumab^# (+deruxtecan / +emtansine) Tucotuzumab celmoleukin^§ Vandortuzumab vedotin^§ Vanucizumab^§ Veltuzumab^§ Vorsetuzumab mafodotin^§
Rat/mouse hybrid	Catumaxomab Ertumaxomab^§
Chimeric + humanized	Depatuxizumab mafodotin^† Duvortuxizumab Ontuxizumab^§

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

Growth factor receptor modulators

Angiopoietin

Agonists: Angiopoietin 1
Angiopoietin 4

Antagonists: Angiopoietin 2
Angiopoietin 3

Kinase inhibitors: Altiratinib
CE-245677
Rebastinib

Antibodies: Evinacumab (against angiopoietin 3)
Nesvacumab (against angiopoietin 2)

CNTF

Agonists: Axokine
CNTF
Dapiclermin

EGF (ErbB)

EGF (ErbB1/HER1)	Agonists: Amphiregulin Betacellulin EGF (urogastrone) Epigen Epiregulin Heparin-binding EGF-like growth factor (HB-EGF) Murodermin Nepidermin Transforming growth factor alpha (TGFα) Kinase inhibitors: Afatinib Agerafenib Brigatinib Canertinib Dacomitinib Erlotinib Gefitinib Grandinin Icotinib Lapatinib Neratinib Osimertinib Vandetanib WHI-P 154 Antibodies: Cetuximab Depatuxizumab Depatuxizumab mafodotin Futuximab Imgatuzumab Matuzumab Necitumumab Nimotuzumab Panitumumab Zalutumumab
ErbB2/HER2	Agonists: Unknown/none Antibodies: Ertumaxomab Pertuzumab Trastuzumab Trastuzumab deruxtecan Trastuzumab duocarmazine Trastuzumab emtansine Kinase inhibitors: Afatinib Lapatinib Mubritinib Neratinib Tucatinib
ErbB3/HER3	Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C)) Antibodies: Duligotumab Patritumab Seribantumab
ErbB4/HER4	Agonists: Betacellulin Epigen Heparin-binding EGF-like growth factor (HB-EGF) Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))

FGF

FGFR1	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20) Repifermin Selpercatinib Trafermin Velafermin
FGFR2	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22) Palifermin Repifermin Selpercatinib Sprifermin Trafermin Antibodies: Aprutumab Aprutumab ixadotin Kinase inhibitors: Infigratinib
FGFR3	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 8, 9, 18, 23) Selpercatinib Sprifermin Trafermin Antibodies: Burosumab (against FGF23)
FGFR4	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 6, 8, 9, 19) Trafermin
Unsorted	Agonists: FGF15/19

HGF (c-Met)

Agonists: Fosgonimeton
Hepatocyte growth factor

Potentiators: Dihexa (PNB-0408)

Kinase inhibitors: Altiratinib
AM7
AMG-458
Amuvatinib
BMS-777607
Cabozantinib
Capmatinib
Crizotinib
Foretinib
Golvatinib
INCB28060
JNJ-38877605
K252a
MK-2461
PF-04217903
PF-2341066
PHA-665752
SU-11274
Tivantinib
Volitinib

IGF

IGF-1	Agonists: des(1-3)IGF-1 Insulin-like growth factor-1 (somatomedin C) IGF-1 LR3 Insulin-like growth factor-2 (somatomedin A) Insulin Mecasermin Mecasermin rinfabate Kinase inhibitors: BMS-754807 Linsitinib NVP-ADW742 NVP-AEW541 OSl-906 Antibodies: AVE-1642 Cixutumumab Dalotuzumab Figitumumab Ganitumab Robatumumab R1507 Teprotumumab Xentuzumab (against IGF-1 and IGF-2)
IGF-2	Agonists: Insulin-like growth factor-2 (somatomedin A) Antibodies: Dusigitumab Xentuzumab (against IGF-1 and IGF-2)
Others	Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7) Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) Trofinetide

LNGF (p75^NTR)

Antagonists: ALE-0540
Dexamethasone
EVT-901 (SAR-127963)
Testosterone

Antibodies: Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab

Aptamers: Against NGF: RBM-004

Decoy receptors: LEVI-04 (p75^NTR-Fc)

PDGF

Agonists: Becaplermin
Platelet-derived growth factor (A, B, C, D)

RET (GFL)

GFRα1	Agonists: Glial cell line-derived neurotrophic factor (GDNF) Liatermin Kinase inhibitors: Vandetanib
GFRα2	Agonists: Neurturin (NRTN) Kinase inhibitors: Vandetanib
GFRα3	Agonists: Artemin (ARTN) Kinase inhibitors: Vandetanib
GFRα4	Agonists: Persephin (PSPN) Kinase inhibitors: Vandetanib
Unsorted	Kinase inhibitors: Agerafenib

SCF (c-Kit)

Agonists: Ancestim
Stem cell factor

TGFβ

See here instead.

Trk

TrkA	Agonists: Amitriptyline BNN-20 BNN-27 Cenegermin DHEA DHEA-S Gambogic amide NGF Tavilermide Antagonists: ALE-0540 Dexamethasone FX007 Testosterone Negative allosteric modulators: VM-902A Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib Milciclib ONO-4474 ONO-5390556 PLX-7486 Rebastinib SNA-120 (pegylated K252a)) Antibodies: Against TrkA: GBR-900; Against NGF: ABT-110 (PG110) ASP-6294 Fasinumab Frunevetmab Fulranumab MEDI-578 Ranevetmab Tanezumab Aptamers: Against NGF: RBM-004 Decoy receptors: ReN-1820 (TrkAd5)
TrkB	Agonists: 3,7-DHF 3,7,8,2'-THF 4'-DMA-7,8-DHF 7,3'-DHF 7,8-DHF 7,8,2'-THF 7,8,3'-THF Amitriptyline BDNF BNN-20 Deoxygedunin Deprenyl Diosmetin DMAQ-B1 HIOC LM22A-4 N-Acetylserotonin NT-3 NT-4 Norwogonin (5,7,8-THF) R7 R13 TDP6 Antagonists: ANA-12 Cyclotraxin B Gossypetin (3,5,7,8,3',4'-HHF) Ligands: DHEA Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486
TrkC	Agonists: BNN-20 DHEA NT-3 Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486