The Antibody Discovery Challenge

The first therapeutic antibody was approved by the FDA in the 1980s – and today the antibody therapy market is flourishing. The year 2021 saw a significant milestone with the FDA’s approval of the 100th monoclonal antibody (mAb). And still the global mAb market grows – from $188.18 billion in 2022 to $209.98 billion in 2023 (a CAGR of 11.6 percent). Over the last three decades, the industry has worked hard to develop a deep evidence base for the safety, manufacturability, and clinical efficacy of mAbs, which has helped make them the most commonly developed biopharmaceuticals. In particular, there has been a steady expansion of therapeutic antibodies against cancer and autoimmune diseases, but these aren’t the only areas where antibodies can make their mark. Looking back to the COVID-19 pandemic – where mAbs were developed as treatments – it is clear that antibodies have a role to play against viral infections, such as influenza, respiratory syncytial virus, and cytomegalovirus.

Founded by scientific experts previously involved in a UK-based antibody taskforce, RQ Bio is a biotech company with its sights set on the discovery and development of mAbs against viral infections. Here, RQ Bio’s CEO, Hugo Fry, and Chief Scientific Officer, Paul Kellam, discuss the challenges of antibody discovery – and why it is so important to consider using antibodies as a tool alongside vaccination to combat infectious disease.

What are the biggest challenges faced when it comes to antibody discovery?
 

Around 11 percent of all human genes encode for proteins that are at the cell membrane – many of which are accessible to antibodies. In addition, all commensal or pathogenic bacteria and viruses encode proteins visible to antibodies. Because each protein has many antibody binding epitopes, the number of potential new antibody targets is vast. What is often lacking,  is deep mechanistic knowledge of the biology and function associated with these proteins in health or disease. Virus proteins that interact with the cell surface are well defined and tractable targets used in drug discovery; however, genetic variation in these proteins creates a challenge in terms of the clinical longevity of an antibody to block infection. Understanding pathogen variation, harnessing antibody diversity, and extending antibody half-life are potential solutions to  the challenges.

What are the most prevalent methods of discovery? 
 

The methods used for antibody discovery and optimization are now routine in academia, large pharma, biotech, and contract research organization laboratories. In the pursuit of finding antibodies with the highest specificity, all methods try to achieve two broad aims: i) to have an exceptionally large diversity of antibodies available to bind the antigen target used for screening, and ii) to ensure that the final antibody is “human” in its amino acid sequence.

Antibody diversity can be obtained from a library of antibodies derived from human white blood cells, which are displayed on phage. Alternatively, diverse antibodies can be produced by immunizing animals with the antigen target and obtaining antigen specific antibody producing cells from the animal.  Antibody expressing cells or phage are then enriched using screening assays against the antigen, followed by sequencing and further characterization of selected hits.

Why is humanization such an important topic?
 

Antibodies from different species vary in amino acid sequences. If animal antibodies are administered to humans, the body recognizes them as foreign. Non-self antibodies  can induce anti-drug antibodies and cause the elimination of the therapeutic antibodies, leading to reduction of  drug efficacy. Thus animal antibodies need to be mutated to “human” amino acid sequences, but this must be done without compromising antibody potency, which can be a complex task. 

If an antibody comes from a human, human antibody phage library, or a humanized animal,  very little  engineering is required. For this reason, human antibody discovery methods are the most popular and preferred approach in the industry.

Where do antibody libraries fit in the picture?
 

Antibody libraries can help capture antibody binding diversity – but, as noted, antibody diversity can also be achieved by mining the immune response in a person or an immunized animal. The important element is the intrinsic diversity of antibodies in the platform being used. Antibody diversity is retained through different germline antibody gene usage and antigen-induced antibody maturation, leading to selection for antibodies with good affinity. These properties are commonly assessed in humans, animals, and phage libraries by sequencing the antibody genes and calculating sequence diversity.

If using the library approach, you can choose to outsource or to develop an in-house platform. Where an antibody discovery platform has been developed in house, with associated licenses and freedom to operate, it is cost effective and productive to use it. However, new companies without their own discovery platforms continue to arise. In these cases, outsourcing to access an established platform to speed discovery is often the best course of action.

Whether outsourcing or using an in-house platform, the reliability of the platform and the skills of operators often dictate success. In addition, the structural authenticity, quality, and purity of the antigen to which antibodies are sought is just as important as the platform itself.

Presumably, starting with the right antigen is also important...
 

That's right. When it comes to viruses, we often know – in exquisite detail – the proteins that initiate infection of cells, as well as the sites on the antigen where antibodies can block cell infection, so called neutralization. Antigens can be used to mine antibodies from the immune response of people who have recovered from infection or from animals previously immunized with the antigen. Therefore, the structural authenticity, quality, and purity of the antigen to which antibodies are sought is just as important as the antibody discovery platform itself. For example, an antigen that functions as a trimeric protein will look different to antibodies when presented to them as a monomer, revealing new and possibly irrelevant antibody binding epitopes – and abolishing others that could be functionally important for antibody activity in a disease. In short, using poor quality or misunderstood antigens is often the root cause of discovery phase failure.

What antibody innovations do you expect to see in the coming years? 
 

We are very interested in using mAbs to protect vulnerable populations against viral infections. For most people, immunity can be achieved by vaccination, where administering a small amount of the antigen can drive “active immunity” in the body to produce  protective antibodies. However, in newborn babies or the elderly, where the immune system is developing or aging respectively, or in vulnerable people, where the immune system is weakened (by other diseases and treatments), active immunization is of limited utility. For these people, passive immunity can be delivered directly by injection of a long-lasting antibody. mAbs, therefore, complete a robust, three-layered prevention of infectious disease: vaccination for all, mAbs for the most vulnerable, and treatment with antivirals for those that require hospitalization. The industry must continue to innovate in all of these areas.

For more information about RQ Bio visit rqbiotechnology.com

The development and manufacture of antibody-based therapeutics has come a long way in the last 30 years – and even today companies are still learning new tips and tricks to optimize discovery processes. Antibody libraries are clearly an important tool in drug developers’ toolboxes that can help identify antibody candidates with the right binding activity. Although mAbs have traditionally been associated with cancer treatments, there is much they can contribute to other therapeutic fields, including infectious diseases. As the industry continues to understand the underlying science behind diseases and develop new discovery tools, the future potential of mAbs will only increase.