Advanced antibodies will revolutionise the future of Immuno-Oncology (IO)
Hannah Hall, Consultant, Citeline, explains how the field of immuno-oncology is poised to transform with the help of advanced antibodies
Immuno-Oncology (IO) is an essential area for biological drug development and has been much talked-about over the past decade. Today, IO therapies represent a third of the biologics pipeline, where antibody development remains the primary focus. In this aspect, the launch of Monoclonal Antibody (MAb) Immune Checkpoint Inhibitors (ICIs) in the past decade has been a game-changer in the industry and provided new treatment routes across the spectrum for solid tumour types and haematological cancers. However, ICIs are limited by the fact they target one singular pathway to mediate T cellcytotoxicity, which means the patient response is low and immune-related adverse events can occur.
This approach does not consider the interactions of other immune cells and complex signalling pathways in the tumour microenvironment. There is, therefore, a great need for more effective and safer drugs that precisely direct cytotoxicity to tumour cells and simultaneously disrupt multiple signalling pathways. Next-generation multi-specific antibodies are designed to do just that, and, are, therefore, anticipated to revolutionise IO in the future.
The biologics market is booming, and the number of pipeline candidates continues to climb the ladder even though development is complex, lengthy and expensive. This has been driven by advances in biotechnology as well as the clear clinical advantages biologics have demonstrated in multiple therapy areas. They have proved to be effective in treating auto-immune conditions, specifically targetting pathogenic immune signalling pathways with fewer side effects compared to small molecules. Their improved target specificity, high efficacy and favourable safety profiles also mark them as revolutionary treatments for cancer.
There have been great advances in understanding the role of immunology in cancer pathogenesis over the past two decades, which has triggered huge industry interest in IO development platforms. The number of IO pipeline candidates has boomed since 2011 when ipilimumab became the first ICI MAb approved for cancer, increasing roughly 15-fold. Over this time, IO has become a significant area of biological therapy development, and IO candidates now represent around a third (33 per cent) of all biologics in development (see Exhibit 1).
There are diverse forms of IOs, including fusion proteins, CAR-T therapies, oncolytic viruses, anti-cancer vaccines and antibodies, which have been investigated over this time period. Antibodies are notably the most popular type of IO in the investigation as they have consistently dominated the development pipeline. Based on data from the last decade, they represent around 40 per cent of IO drugs in development per year on average (Exhibit 2).
So far, clinical development programmes for IO drugs have proven significantly more successful than those for traditional oncology drugs. Biomedtracker estimates that the Likelihood Of Approval (LOA) of an IO candidate in phase-I is significantly higher than the average oncology candidate LOA (12.4 per cent vs. 5.3 per cent). Moreover, IO drugs have a notably high phase-II to phase-III transition rate of 42 per cent, compared to 24.6 per cent for the general oncology pipeline. To date, there have been 55 IOs approved, and the rapid growth and depth of the development pipeline will lead to more becoming available to patients in the future.
The current pipeline and next-generation antibodies
As of April 2022, there are currently 2,809 IO therapies in development. The pipeline mostly consists of very early-stage candidates, with ~62 per cent (N=1,759) of all drugs in pre-clinical stages. There are 1,035 drugs in clinical trials, and 15 are awaiting approval in pre-registration phase (see Exhibit 2).
Almost all the candidates in the pipeline are novel chemical or biological entities as there are just 19 biosimilars in development, including ipilimumab, nivolumab and pembrolizumab and rituximab biosimilars.
After the success of MAbs in cancer therapy, it is not surprising that antibodies remain the most common type of IO in development, with 411 currently in clinical trials. Over a third (N=147/411) of these are next-generation multi-specific antibodies, which target multiple antigens or epitopes on the same antigen. These antibodies are promising as they can be designed to target multiple cells in the tumour microenvironment, rather than a singular molecular pathway. They aim to influence tumour death through various mechanisms including T cell costimulation, engagement of innate and adaptive immune cells, inhibition of specific mutation-driven signalling pathways, simultaneous blockade of two immune checkpoints, and targetting multiple antigens to increase tumour selectivity. Considering their specificity and unique targeting capabilities, it is likely that these drugs will prove more effective and safer than current MAbs and entry of these drugs into the market could revolutionise IO. Furthermore, as our understanding of the complex interactions between tumour and immune cells in the TME advances, it is likely we will identify new targets and immune signatures specific to certain cancer types and individuals. Cancer treatment is inexorably becoming more personalised, and, one day, it may be possible that IO therapy combinations can be routinely tailored for patients based on their specific immune signature. As the depth of investigation into multi-specific antibodies increases, these powerful drug classes can be adapted to new target combinations in the future, and, therefore, they will play an important role in personalised combination therapy.
As IO development has boomed, antibody drugs have proved themselves as pivotal tools in cancer therapy. The arrival of ICI MAbs has been trailblazing in the field and provided much-needed new treatment choices for patients; advances in antibody research and development in IO will lead to the next generation of cancer therapies. Current ICIs are limited by low response rates and association with immune adverse events. Therefore, a major goal of developers in the IO space is to build on the success of MAbs and advance antibody technology to discover new therapies with improved safety and efficacy. Multi-specific antibodies are particularly promising as they can be designed to simultaneously target multiple pathogenic pathways, and, hence, are a major focus of development currently, and, as the industry anticipation is concerned, they will revolutionise IO as they enter the market in the future.