Antibody-drug conjugate

Antibody-drug conjugates (ADCs) are a new type of targeted therapy, used for example for cancer.^[1][2][3][4] They consist of an antibody (or antibody fragment such as a single-chain variable fragment [scFv]) linked to a payload drug (often cytotoxic).^[5] 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.^[6] Because of the targeting, the side effects should be lower and give a wider therapeutic window.^[7]

Hydrophilic linkers (e.g., PEG4Mal) help prevent the drug being pumped out of resistant cancer cells through MDR (multiple drug resistance) transporters.^[5]

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.^[8]

Companies developing the underlying technology for ADCs include^[9]:

• Seattle Genetics^[10] of Bothell, Washington, in deals with Pfizer, Abbott,^[11] Roche/Genentech^[8] etc, for their toxins and non-cleavable linkers
• ImmunoGen Inc of Waltham, Massachusetts, in deals with Novartis and Roche/Genentech for their tumor-activated prodrug (TAP) linker technology
• Spirogen Ltd^[12] of London, UK, in deals with Genentech,^[13]

Approvals and indications

• gemtuzumab ozogamicin (Mylotarg) Approved for acute myelogenous leukemia in 2001 but since withdrawn.
• brentuximab vedotin (Adcetris) Approved for relapsed and refractory hodgkin lymphoma and anaplastic large cell lymphoma.

Examples in clinical trials

(based on^[1][7][14])

Late stage

Phase III trials initiated:

• Trastuzumab emtansine (T-DM1) (Herceptin linked to DM1)^{[5][7][15][16]} for breast cancer, especially HER2+.^[17]
• Inotuzumab ozogamicin (CMC-544) for non-Hodgkin lymphoma.

Phase II initiated:

• Glembatumumab vedotin (CDX-011, CR011-vcMMAE) for melanoma and metastatic breast cancer.
• lorvotuzumab mertansine (IMGN901) for CD56 cancers (e.g. small-cell lung cancer, ovarian cancer).^[5][18] Orphan drug for Merkel cell carcinoma^[19] Phase II results for small-cell lung cancer^[20]
• IMGN242^[21] for CanAg expressing gastric cancer.
• AN-152^[7]p9, (AEZS-108) doxorubicin linked to [D-Lys(6)]- LHRH, Results for ovarian cancer^[22]
• LMB2, TP-38, VB4-845^[7]p9

Early stage

Phase I trials initiated:

• Cantuzumab mertansine (huC242-DM1) Results^[23]
• AVE9633, anti-CD33 antigen, disulphide linked to DM4^[24]
• SAR3419, with results for B-cell non-Hodgkin’s lymphoma (NHL).^[25]
• CAT-8015 (anti-CD22)
• IMGN388 : integrin-targeting against solid tumors^[5] tried on 4 cancer patients^[26]
• milatuzumab-doxorubicin for relapsed multiple myeloma.^[27]
• SGN-75 (anti-CD70) for non-Hodgkin lymphoma or renal cell carcinoma^[28][29]
• AGS-16M8F, for renal cell carcinoma.^[30]

Preclinical trials initiated:

• Anti-CD22-MCC-DM1 for leukemia^[31]
• and others.^[7]
• ASG-22ME, which targets the Nectin-4 antigen.^[30]

References