spacer
home > ebr > summer 2018 > the future of adcs
PUBLICATIONS
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 Early technology pioneers developed Mylotarg to treat acute myeloid leukaemia (Pfizer – initially withdrawn due to toxicity, but recently reintroduced to the market), Kadcyla® (Genentech) to treat metastatic breast cancer, Adcetris® to treat Hodgkin’s Lymphoma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).

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer
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.
spacer
Dr Neil Butt
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

Protagen Protein Services (PPS) reaches new level in characterizing HCP protein impurities

In response to current regulatory guidance a Mass Spectrometry (MS) based Host Cell Protein (HCP) detection approach with faster, more accurate and wider-ranging detection is essential. In order to meet the newly prevailing demands Protagen Protein Services (PPS) recently invested in more far-reaching MS capabilities: The new high-performing mass spectrometer ThermoFisher Q Exactive™ HF-X started operational service last month and brings PPS to the next level of reproducible, accurate and sensitive analyses of majorly complex samples for different aspects of translational research and biopharma applications.
More info >>

White Papers

Key to Outsourcing Method Development and Validation: A Pragmatic Approach

RSSL

In an industry that is seeing an increasing level of work being outsourced, the Contract Research Organisation (CRO) of choice needs to have proven experience in both the pragmatism and flexibility of the method developer’s mind set and a regulatory background in validation. As companies are focussing on achieving ever shorter times of drug to market, it is vital that a tailored, pragmatic approach is adopted when engaging in both method development and validation activities for an Active Pharmaceutical Ingredient (API) or drug product (DP). Although methods still require a high degree of robustness, the overall strategy should encompass a full evaluation of the regulatory requirements applicable to the particular phase of the drug life-cycle; this is pivotal in Key to Outsourcing Method Development and Validation A Pragmatic Approach order to ensure a successful regulatory submission, where the applicant must demonstrate suitable validation of all methods used to support the filing.
More info >>

 
Industry Events

Multimodal 2019

18-20 June 2019, NEC, Birmingham, UK

Now in its twelfth year, Multimodal is the UK and Ireland’s premier freight transport, logistics and supply chain management event.  Shippers and cargo owners attend to improve their businesses; by finding ways of moving their products more efficiently and by meeting new suppliers. 
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement