Identification

Name
Olaratumab
Accession Number
DB06043
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Olaratumab (IMC-3G3) is a fully human IgG1 monoclonal antibody with antitumor activity that selectively binds the external domain of human platelet-derived growth factor receptor (PDGFR)-α with high affinity and blocks ligand binding. It is composed of two heavy chain molecule fragments and 2 light chain fragments. Studies show that the treatment of olaratumab in combination with doxorubicin resulted in significant reduction of cancer cell proliferation and tumor growth. Olaratumab was granted accelerated approval (as Lartruvo) as initial therapy to treat adults with certain types of soft tissue sarcoma (STS) in October, 2016.

Protein chemical formula
C6554H10076N1736O2048S40
Protein average weight
154000.0 Da (147200 Da without glycan mass/154600 Da with glycan mass)
Sequences
>Heavy Chain
QLQLQESGPGLVKPSETLSLTCTVSGGSINSSSYYWGWLRQSPGKGLEWIGSFFYTGSTY
YNPSLRSRLTISVDTSKNQFSLMLSSVTAADTAVYYCARQSTYYYGSGNYYGWFDRWDQG
TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP
APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK
PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL
TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Light Chain
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPAFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
Not Available
External IDs
IMC-3G3
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LartruvoSolution500 mgIntravenousEli Lilly & Co. Ltd.2017-12-22Not applicableCanada
LartruvoInjection, solution10 mg/1mLIntravenousEli Lilly and Company2016-10-19Not applicableUs
LartruvoInjection, solution10 mg/1mLIntravenousEli Lilly and Company2016-10-19Not applicableUs
International/Other Brands
Lartruvo
Categories
UNII
TT6HN20MVF
CAS number
1024603-93-7

Pharmacology

Indication

Olaratumab is indicated, in combination with doxorubicin, for the treatment of adult patients with advanced or mestastatic soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

Associated Conditions
Pharmacodynamics

It exerts an anti-tumor activity in vivo and in vitro against selected sarcoma cells by inhibiting tumor growth by binding to PDGFR-alpha that is present on several types of cancer on transformed cells and in tumor stroma [3]. Olaratumab antibody binding leads to inhibition of ligand-dependent signaling in PDGFR(alpha)-expressing tumor cells, as well as stromal cells in the tumor microenviroment that are dependent on PDGFR(alpha) signaling. When used in a combination therapy with doxorubicin, olaratumab improves progression-free survival in patients with advanced soft-tissue sarcoma.

Mechanism of action

Olaratumab blocks ligand-induced tumor cell proliferation, and inhibits receptor autophosphorylation and ligand-induced phosphorylation of the downstream signaling molecules protein kinase B (Akt) and mitogen-activated protein kinase [5]. PDGFR signalling is a type of tyrosine kinase-mediated pathway that normally regulates cell growth, chemotaxis, and mesenchymal stem cell differentiation. It also promotes internalization of PDGFR thus alters the surface levels of PDGFR.

TargetActionsOrganism
APlatelet-derived growth factor receptor alpha
antagonist
Human
Absorption
Not Available
Volume of distribution

7.7 L at steady state.

Protein binding

None

Metabolism

Mainly degraded nonspecifically by proteolytic enzymes

Route of elimination
Not Available
Half life

Estimated value of 11 days

Clearance

Mean value of 0.56L/day

Toxicity

Infusion-related reactions may occur during or after the administration which include bronchospasm, flushing, hypotension, anaphylactic shock, or cardiac arrest. Olaratumab may cause embryo-fetal toxicity based on animal data and its mechanism of action. Other reported adverse effects include neutropenia, leukopenia, anemia, nausea and musculoskeletal pain.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Olaratumab.
AbituzumabThe risk or severity of adverse effects can be increased when Olaratumab is combined with Abituzumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Olaratumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Olaratumab.
AducanumabThe risk or severity of adverse effects can be increased when Olaratumab is combined with Aducanumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Olaratumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Olaratumab.
AlirocumabThe risk or severity of adverse effects can be increased when Olaratumab is combined with Alirocumab.
AmatuximabThe risk or severity of adverse effects can be increased when Olaratumab is combined with Amatuximab.
AMG 108The risk or severity of adverse effects can be increased when AMG 108 is combined with Olaratumab.
Food Interactions
Not Available

References

General References
  1. Dolloff NG, Russell MR, Loizos N, Fatatis A: Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the alpha-platelet-derived growth factor receptor. Cancer Res. 2007 Jan 15;67(2):555-62. [PubMed:17234763]
  2. Shirley M: Olaratumab: First Global Approval. Drugs. 2016 Dec 19. [PubMed:27995580]
  3. Doi T, Ma Y, Dontabhaktuni A, Nippgen C, Nippgen J, Ohtsu A: Phase I study of olaratumab in Japanese patients with advanced solid tumors. Cancer Sci. 2014 Jul;105(7):862-9. doi: 10.1111/cas.12444. Epub 2014 Jun 27. [PubMed:24816152]
  4. Knepper TC, Saller J, Walko CM: Novel and Expanded Oncology Drug Approvals of 2016-PART 1: New Options in Solid Tumor Management. Oncology (Williston Park). 2017 Feb 15;31(2):110-21. [PubMed:28205191]
  5. Wagner AJ, Kindler H, Gelderblom H, Schoffski P, Bauer S, Hohenberger P, Kopp HG, Lopez-Martin JA, Peeters M, Reichardt P, Qin A, Nippgen J, Ilaria RL, Rutkowski P: A phase II study of a human anti-PDGFRalpha monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors. Ann Oncol. 2017 Mar 1;28(3):541-546. doi: 10.1093/annonc/mdw659. [PubMed:28426120]
  6. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria R Jr, Conti I, Cosaert J, Schwartz GK: Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016 Jul 30;388(10043):488-97. doi: 10.1016/S0140-6736(16)30587-6. Epub 2016 Jun 9. [PubMed:27291997]
External Links
KEGG Drug
D09939
PubChem Substance
347910322
ChEMBL
CHEMBL1743049
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Olaratumab
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (355 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentNeoplasms1
1Active Not RecruitingTreatmentSoft Tissue Sarcoma (STS)1
1CompletedNot AvailableTumors, Solid1
1CompletedBasic ScienceSoft Tissue Sarcoma (STS)1
1CompletedTreatmentMalignancies / Metastasis1
1Not Yet RecruitingTreatmentLeiomyosarcomas1
1RecruitingBasic ScienceSoft Tissue Sarcoma Adult1
1RecruitingTreatmentNeoplasms Metastasis1
1RecruitingTreatmentSoft Tissue Sarcoma (STS)2
1, 2RecruitingTreatmentPancreatic Cancer Metastatic1
1, 2RecruitingTreatmentSoft Tissue Sarcoma (STS)1
1, 2Unknown StatusTreatmentSoft Tissue Sarcoma (STS)1
2CompletedTreatmentAdult Glioblastoma Multiforme / Brain and Central Nervous System Tumors1
2CompletedTreatmentGastrointestinal Stromal Tumors (GISTs)1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentNeoplasms, Ovarian1
2CompletedTreatmentProstate Cancer1
2Not Yet RecruitingTreatmentAdvanced Soft Tissue Sarcoma1
2Not Yet RecruitingTreatmentSoft Tissue Sarcoma (STS)1
2RecruitingTreatmentEpithelioid Sarcoma / Fibrosarcomas malignant / Hemangiosarcoma / Leiomyosarcomas / Liposarcoma / Malignant Peripheral Nerve Sheath Tumour (MPNST) / Myxofibrosarcoma / Soft Tissue Sarcoma (STS) / Synovial Sarcoma / Undifferentiated Pleomorphic Sarcoma1
3Active Not RecruitingTreatmentSoft Tissue Sarcoma (STS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous10 mg/1mL
SolutionIntravenous500 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chem...
Gene Name
PDGFRA
Uniprot ID
P16234
Uniprot Name
Platelet-derived growth factor receptor alpha
Molecular Weight
122668.46 Da
References
  1. van der Graaf WT: Olaratumab in soft-tissue sarcomas. Lancet. 2016 Jul 30;388(10043):442-4. doi: 10.1016/S0140-6736(16)30788-7. Epub 2016 Jun 9. [PubMed:27291995]
  2. Doi T, Ma Y, Dontabhaktuni A, Nippgen C, Nippgen J, Ohtsu A: Phase I study of olaratumab in Japanese patients with advanced solid tumors. Cancer Sci. 2014 Jul;105(7):862-9. doi: 10.1111/cas.12444. Epub 2014 Jun 27. [PubMed:24816152]

Drug created on November 18, 2007 11:29 / Updated on November 14, 2018 12:53