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European Biopharmaceutical Review

The Future of ADCs

Targeted therapeutics, as conceived by Paul Ehrlich at the turn of the last century, are now a reality with the world’s best-selling drug (Humira) paving the way for increased development in the biologics field. The subsequent development of antibody-based therapeutics opened the floodgates for a variety of targeted drugs (eg, bispecifics, bi-specific T-cell engagers, designed ankyrin repeat proteins, etc) to be developed and to expand upon the therapeutic opportunities. Antibody-drug conjugates (ADCs) now also appear to be capturing the limelight.

The use of cytotoxic compounds to target cancer cells has been the mainstay of cancer treatment for over 50 years. Chemotherapy using cytoxic compounds (both as single compounds and in combination therapies) have been optimised to maximise patient benefit (1). However, these agents are limited by systemic toxicity and poor tumour penetration, resulting in the risk of relapse and the need for further treatment. The simple concept of monoclonal antibodies targeting tumour-specific antigens being joined to cytotoxic agents to kill cancer cells has been muted for many years. Early technology pioneers developed Mylotarg to treat acute myeloid leukaemia (Pfizer – initially withdrawn due to toxicity, but recently reintroduced to the market), Kadcyla® (Genentech) to treat metastatic breast cancer, Adcetris® to treat Hodgkin’s Lymphoma (Seattle Genetics), and, more recently, Besponsa® (Pfizer), but these are widely considered to have drawbacks (2-3). One challenge for ADCs has been obtaining a reasonable therapeutic window where the toxicity conveyed by factors such as instability or off-site binding outweighs the clinical benefit. To overcome such challenges, new technologies are emerging that address the three fundamental components of these molecules: the antibody, the cytotoxic payload, and the linker that joins all the components together (see Figure 1). With each technology iteration associated with these three components improving efficacy and safety, the prospect for this class of therapies is bright. This article will discuss the new technologies emerging that may address the shortfalls in early ADC development and thereby increase the numbers gaining approval.

Selection of Antibodies

The selection of an appropriate antibody is still a vague science associated with development of a suitable ADC. Antibody specificity to minimise off-site binding and to generate as large a therapeutic index as possible is of critical importance. Further to this, internalisation of the antibody is also vital to ensure the toxic payload is delivered to the appropriate location. The required affinity of the base antibody has been reported to be of lesser importance, with high affinity antibodies sticking to the surface of tumour cells resulting in limited tumour penetration, whereas lower affinity antibodies have been shown to reflect better tumour penetration (4-5). To date, most ADCs have affinities in the range of 0.1-1nM, but the uncertainty surrounding the best antibody selection suggests the testing of large panels of antibodies with diverse affinities may be the most rational strategy during early development. As ADCs evolve, other contributing features to enhance function are also being considered. For example, the use of an IgG1 isotype may encourage antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complementdependent cytotoxicty (CDC) activity and additional cell lysis. Such activity may subsequently lead to cytotoxic metabolites or released cytotoxic payload diffusing into surrounding cells and assisting cell killing in the tumour environment − the so-called ‘bystander effect’ (9).

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Dr Neil Butt has over 20 years’ experience in the biotechnology industry, covering both research and business development. His industrial experience started in R&D before joining PA Consulting where he focused on business development and operational roles in the biotech sector. Neil then joined the executive management team of Antitope as Head of Business Development. During his tenure, he was key to the company’s growth and helped steer them through the acquisition by Polytherics. Neil was then appointed Head of Business development and was part of the executive management team that oversaw the rebranding as Abzena. He joined IONTAS in 2016 as Chief Business Officer.
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