ANTIBODY-DRUG CONJUGATE
To date, four ADCs have received market approval. Gemtuzumab ozogamicin for treatment of acute myelogenous leukemia, Brentuximab vedotin for treatment of relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), Trastuzumab emtansine for tratment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC), and Inotuzumab ozogamicin for treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL).
Integrated Solutions for ADC Development Provided by Creative Biolabs
Monoclonal antibody
·Antibody properties ·Internalization ·Receptor-mediated endocytosis
Cytotoxic payload
·Microtuble inhibitors -Auristatins -Maytansines ·DNA synthesis inhibitors -Calicheamicm -Doxorubicin -Duocarmycine -Pyrrolobenzodiazepine ·Topoisomerase inhibitors -Quinoline alkaloids
Linker
·Cleavable -Acid-labile -Protease cleavable -Disulphide linkage ·Non-cleavable -Thioether -Maleimidocaproyl
Mechanism of action of ADC
2
Route 2 Inhibite microtubles
ADC Microtubules
In
Route 1 Nucleus
Tumor cell
on
zati
ali tern
Route 3 Inhibite topoisomerase
3
Route 2
e
ing
nd Bi
ut
Antibodies track these proteins down in the body and attach themselves to the surface of cancer cells. The biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the tumor cell, which then absorbs or internalizes the antibody together with the cytotoxin. After the ADC is internalized, the cytotoxic drug is released and kills the cancer cell. By combining the targeting capabilities of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs, antibody-drug conjugates allow for discrimination between healthy and diseased tissue.
Structure of antibody-drug conjugate (ADC)
1
Ro
Antibody-Drug Conjugates (ADCs) are monoclonal antibodies (mAbs) attached to biologically active drugs (cytotoxic payloads) by chemical linkers with labile bonds.
Route 1 Inhibite DNA synthesis
e
as
le Re
Degradation
Endosome
3
Lysosome
Approved ADC Products for marketing
Name
Trade name
Therapeutic area
Company
First approval date
Gemtuzumab ozogamicin
Mylotarg
Acute myelogenous leukemia
Wyeth Pharms Inc.
May 11, 2000 (withdraw 2010)
Brentuximab vedotin
Adcetris
Relapsed or refractory HL and systemic ALCL
Seattle Genetics
August 19, 2011
Trastuzumab emtansine
Kadcyla
HER2-positive mBC
Genentech
February 22, 2013
Inotuzumab ozogamicin
Besponsa
Wyeth Pharms Inc.
August 17, 2017
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Relapsed or refractory CD22positive B-cell precursor ALL
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