Antibody-drug conjugate
Encyclopedia
Antibody-drug conjugates (ADCs) are a new type of targeted therapy
, used for example for cancer
. They consist of an antibody
(or antibody fragment such as a single-chain variable fragment [scFv]) linked to a payload drug (often cytotoxic). Hence, they are a type of immunoconjugate
and often an immunotoxin
.
The antibody causes the ADC to bind to the target cancer cells. Often the ADC is then internalized by the cell and the drug is released to do its damage. Because of the targeting, the side effects should be lower and give a wider therapeutic window
.
Hydrophilic linkers (e.g., PEG4Mal) help prevent the drug being pumped out of resistant cancer cells through MDR (multiple drug resistance) transporters.
ADCs based on cleavable linkers are thought to have a less favorable therapeutic window,
but targets (tumor cell surface antigens) that do not get internalized efficiently seem more suitable for cleavable linkers.
Companies developing the underlying technology for ADCs include:
Phase II initiated:
Preclinical trials initiated:
Targeted therapy
Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...
, used for example for cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. They consist of an antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
(or antibody fragment such as a single-chain variable fragment [scFv]) linked to a payload drug (often cytotoxic). Hence, they are a type of immunoconjugate
Immunoconjugate
Immunoconjugates are antibodies conjugated to a second molecule, usually a toxin, radioisotope or label.These conjugates are used in immunotherapy and to develop monoclonal antibody therapy as a targeted form of chemotherapy when they are often known as antibody-drug conjugates.When the conjugates...
and often an immunotoxin
Immunotoxin
An immunotoxin is a human-made protein that consists of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell...
.
The antibody causes the ADC to bind to the target cancer cells. Often the ADC is then internalized by the cell and the drug is released to do its damage. Because of the targeting, the side effects should be lower and give a wider therapeutic window
Therapeutic window
The Therapeutic window of a drug is the range of drug dosages which can treat disease effectively while staying within the safety range. In other words, it is the dosages of a medication between the amount that gives an effect and the amount that gives more adverse effects than desired effects...
.
Hydrophilic linkers (e.g., PEG4Mal) help prevent the drug being pumped out of resistant cancer cells through MDR (multiple drug resistance) transporters.
ADCs based on cleavable linkers are thought to have a less favorable therapeutic window,
but targets (tumor cell surface antigens) that do not get internalized efficiently seem more suitable for cleavable linkers.
Companies developing the underlying technology for ADCs include:
- Seattle Genetics of Bothell, Washington, in deals with PfizerPfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
, AbbottAbbottAbbott is a title given to the head of a monastery.Abbott may also refer to:-People:* Abbott , for people named Abbott* Abbott Handerson Thayer , American painter and naturalist-Places in the United States:* Abbott, Arkansas...
, Roche/GenentechGenentechGenentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
etc, for their toxins and non-cleavable linkers - ImmunoGen Inc of Waltham, Massachusetts, in deals with NovartisNovartisNovartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
and Roche/Genentech for their tumor-activated prodrug (TAP) linker technology - Spirogen Ltd of London, UK, in deals with GenentechGenentechGenentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
,
Approvals and indications
- gemtuzumab ozogamicinGemtuzumab ozogamicinGemtuzumab ozogamicin is a drug-linked monoclonal antibody that was used to treat acute myelogenous leukemia from 2000-2010...
(Mylotarg) Approved for acute myelogenous leukemia in 2001 but since withdrawn. - brentuximab vedotinBrentuximab vedotinBrentuximab vedotin is an antibody-drug conjugate approved to treat anaplastic large cell lymphoma and Hodgkin lymphoma. The U.S...
(Adcetris) Approved for relapsed and refractory hodgkin lymphoma and anaplastic large cell lymphomaAnaplastic large cell lymphomaAnaplastic large-cell lymphoma is a type of non-Hodgkin lymphoma that features in the World Health Organisation classification of lymphomas.Its name derives from anaplasia and large-cell lymphoma.-Signs and symptoms:...
.
Late stage
Phase III trials initiated:- Trastuzumab emtansineTrastuzumab emtansineTrastuzumab emtansine is an antibody-drug conjugate consisting of the antibody trastuzumab linked to the cytotoxin mertansine ....
(T-DM1MertansineMertansine is a cytotoxic agent also known as DM1. It is a maytansinoid .Its patent rights are owned by ImmunoGen Inc.- Uses :...
) (Herceptin linked to DM1) for breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, especially HER2+. - Inotuzumab ozogamicinInotuzumab ozogamicinInotuzumab ozogamicin is a humanized monoclonal antibody for the treatment of cancers. The monoclonal antibody is linked to a cytotoxic agent from the class of calicheamicins ....
(CMC-544) for non-Hodgkin lymphomaNon-Hodgkin lymphomaThe non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
.
Phase II initiated:
- Glembatumumab vedotinGlembatumumab vedotinGlembatumumab vedotin is an antibody-drug conjugate that targets cancer cells expressing transmembrane glycoprotein NMB ....
(CDX-011, CR011-vcMMAE) for melanomaMelanomaMelanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and metastatic breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. - lorvotuzumab mertansineLorvotuzumab mertansineLorvotuzumab mertansine is an antibody-drug conjugate of lorvotuzumab linked to mertansine intended for CD56 positive cancers .It has been granted Orphan drug status for Merkel cell carcinoma....
(IMGN901) for CD56 cancers (e.g. small-cell lung cancer, ovarian cancer). Orphan drug for Merkel cell carcinomaMerkel cell carcinomaMerkel cell carcinoma Merkel cell carcinoma Merkel cell carcinoma (also known as a "Cutaneous apudoma," "Primary neuroendocrine carcinoma of the skin," "Primary small cell carcinoma of the skin," and "Trabecular carcinoma of the skin"...
Phase II results for small-cell lung cancer - IMGN242 for CanAg expressing gastric cancer.
- AN-152p9, (AEZS-108) doxorubicin linked to [D-Lys(6)]- LHRH, Results for ovarian cancer
- LMB2, TP-38, VB4-845p9
Early stage
Phase I trials initiated:- Cantuzumab mertansineCantuzumab mertansineCantuzumab mertansine is a humanized monoclonal antibody used to treat colorectal cancer and other types of cancer. It is linked to a cytotoxic agent, mertansine.Three phase I clinical studies had reported results by 2003....
(huC242-DM1MertansineMertansine is a cytotoxic agent also known as DM1. It is a maytansinoid .Its patent rights are owned by ImmunoGen Inc.- Uses :...
) Results - AVE9633, anti-CD33 antigen, disulphide linked to DM4
- SAR3419, with results for B-cell non-Hodgkin’s lymphoma (NHL).
- CAT-8015Anti-CD22 immunotoxinAnti-CD22 immunotoxin is a monoclonal antibody linked to a toxic substance. They are being studied in the treatment of some types of B-cell cancer....
(anti-CD22) - IMGN388 : integrinIntegrinIntegrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
-targeting against solid tumors tried on 4 cancer patients - milatuzumabMilatuzumabMilatuzumab is a monoclonal antibody for the treatment of multiple myeloma and other hematological malignancies.This drug was developed by Immunomedics, Inc....
-doxorubicinDoxorubicinDoxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
for relapsed multiple myelomaMultiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
. - SGN-75 (anti-CD70) for non-Hodgkin lymphomaNon-Hodgkin lymphomaThe non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
or renal cell carcinomaRenal cell carcinomaRenal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases... - AGS-16M8F, for renal cell carcinomaRenal cell carcinomaRenal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
.
Preclinical trials initiated:
- Anti-CD22-MCC-DM1 for leukemiaLeukemiaLeukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
- and others.
- ASG-22ME, which targets the Nectin-4 antigen.