Antibody-drug conjugates (ADCs)

ADCs have finally come of age: Dr Marshall Pearce

Over the past couple of decades, there have been advances in a class of drugs which for a long time was purely theoretical: antibody-drug conjugates (ADCs). The concept underlying ADCs is elegant – what if it were possible to ‘target’ particular groups of cells with a cytotoxic agent, rather than exposing every cell of the body to it? To accomplish this, a monoclonal antibody can be attached to a cytotoxic drug via a ‘linker’ – the antibody is specific for an antigen expressed exclusively, or at least in greater concentration, on the target cells. Once the antibody has bound to the antigen, the complex is internalised into the target cell, decoupling the linkage mechanism – freeing the cytotoxic molecule and resulting in cell death. This enables potent drugs with a narrow therapeutic window to be used, and can theoretically mitigate systemic side-effects.

Figure 1. Diagrammatic representation of the mechanism of action of an ADC.

Challenges

Although the theory is relatively straightforward, the implementation has proven to be very complex, with many unknowns and challenges to be addressed:

Antigen

Determining which antigen can be targeted is the initial step. The ideal target antigen needs to be highly expressed with limited heterogeneity, have low expression in non-targeted tissues, and not become down-regulated after treatment with ADCs. Tumour-specific antigens are ideal, yet most targets to date have been tumour-associated antigens – HER2 is the antigen targeted by trastuzumab emtansine in breast cancer, and needs to be very highly expressed in a tumour to avoid exposing normal tissues to damage.

Antibody

Breakthroughs in recent years have made it feasible to use monoclonal antibodies as one of the basic components of ADCs. Humanised antibodies can be created, rather than using animal alternatives which may provoke an immune response. IgG is the most commonly used antibody for this purpose. The action of the antibody itself also must be considered, if it has a cytotoxic effect, or prevents internalisation of the ADC, the surrounding tissue may be exposed to the effects of the cytotoxic “payload”.

Linker

The properties of the linkage mechanism between the antibody and the cytotoxic drug plays a significant role in determining the safety, specificity, potency and activity of an ADC. The ideal linker is stable in the bloodstream, then easily broken down within the target cell – delivering the payload. How many drug molecules are attached to each antibody also influences the activity of the drug, and the optimal strategy varies. It is primarily through recent advances in linker technology that ADCs have become viable.

Cytotoxic agent

In practice, only small amounts of the cytotoxic payload reach the tumour – necessitating a highly potent agent, yet one that must remain stable prior to delivery. Different drugs have been used for this purpose, including well-established cytotoxic agents and highly potent cytotoxic compounds with a therapeutic index too narrow for untargeted use.

Figure 2. Illustration of an ADC molecule.

Practical application

In practice, there are two currently approved ADCs: trastuzumab emtansine (Kadcyla) for breast cancer, and brentuxumab vedotin (Adcetris) for some forms of lymphoma. A third ADC, gemtuzumab ozogamicin (marketed as Mylotarg), was previously approved for use in acute myelogenous leukaemia but was withdrawn in 2010 following trials demonstrating an increased mortality and incidence of serious adverse events, and limited efficacy over conventional therapies. However, in early 2017 it was submitted to the FDA and EMA for re-approval based on new trial data and a meta-analysis of earlier studies.

Trastuzumab emtansine was approved in 2013 by the FDA and the EMA, and has demonstrated superior progression-free survival in HER2-positive advanced breast cancer. Subsequent trials for additional indications have not demonstrated a clear survival benefit over existing treatments. The high cost has at times been a prohibitive factor, preventing reimbursement by the UK’s National Institute of Health and Care Excellence (NICE), for example.

Brentuxumab vedotin was approved by the FDA in 2011, and by the EMA in 2012, for relapsed cases of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. As it targets the CD30 antigen, which is expressed on other lymphomas, it has potential for more widespread application. Given the scarcity of treatments for relapse of these conditions, brentuxumab vedotin has a significant role to play at present. The five-year end study results for the initial phase II trial have even suggested that it may have demonstrated a curative effect in relapsed Hodgkin’s lymphoma; 9% of the study population remained in remission at 5 years, despite no further treatment.

Inotuzumab ozogamicin completed a phase 3 trial (INO-VATE) which reported in June 2016, and demonstrated a significantly higher complete remission rate, longer progression free survival, and longer overall survival versus standard chemotherapy in acute lymphoblastic leukaemia (ALL). There was a higher incidence of veno-occlusive liver disease in the treatment arm. Following a positive recommendation from the EMA's Committee for Medicinal Products for Human Use in April 2017, the drug was approved as monotherapy for ALL by the European Commission in July 2017, under the brand name Besponsa. It is currently under review by the FDA, with a decision expected in August 2017.

Future potential

Although there are many potential therapies in the pipeline (table 1), there are only three which are currently in late-stage trials:

Depatuxizumab mafodotin has been granted orphan status, and is currently in phase II/III trials for the treatment of glioblastoma. Its efficacy has yet to be clearly established, and optimal dosing has not yet been calculated. A meta-analysis of early data suggested that there was no improvement in overall survival, and although progression-free survival was better than standard treatment, there were a higher number of adverse events.

Vadastuximab tariline is undergoing a phase 3 trial (CASCADE) to determine efficacy in acute myeloid leukaemia. The phase I trials reported to date studied older patients with AML who had declined intensive treatment, demonstrating good remission rates and that it was generally well tolerated. Counter to this, as of December 2016, a hold has been placed on several existing phase I trials by the FDA to evaluate potential hepatotoxicity.

Mirvetuximab soravtansine began phase III trials (FORWARD I) in January 2017 to determine efficacy as a sole agent for folate receptor alpha positive ovarian cancer. It has been granted orphan status, and phase I studies have demonstrated efficacy in the laboratory setting.

Summary

ADCs have not immediately proven to be the magic bullet that may have been hoped for, but expectations must be tempered, as they are very much a developing treatment. The only practical application to date has been in malignancy, although the theory could be applied to any cell type with a targetable antigen. It has been suggested that ADCs may play a role as antibacterials, which could prove a viable strategy in the face of the increasing antibiotic resistance.

Reference materials for further reading

ADC review: Journal of antibody-drug conjugates. What are antibody-drug conjugates? http://adcreview.com/adc-university/adcs-101/antibody-drug-conjugates-adcs/ [accessed 06/03/2017]

Bouchard H, Viskov C, Garcia-Echeverria C. Antibody–drug conjugates—A new wave of cancer drugs. Bioorg Med Chem Lett. 2014 Dec 1;24(23):5357-63.

Diamantis N, Banerji U. Antibody-drug conjugates--an emerging class of cancer treatment. Br J Cancer. 2016 Feb 16;114(4):362-7.

Kim EG, Kim KM. Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics. Biomol Ther (Seoul). 2015 Nov;23(6):493-509.

Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015 Jun 12;35(4).