By Hannah Hall
In the past ten years, the field of immuno-oncology (IO) has experienced incredible growth. Currently, a third of the biologics pipeline consists of IO therapies, and antibody development, which remain to be priorities. Additionally, over the same period of time, with the development of monoclonal antibody (MAb) immune checkpoint inhibitors (ICIs) has become a game changer in the industry and has opened up new treatment options for a variety of solid tumours and haematological cancers.
While revolutionary in their own way, ICIs are limited by the fact that they target a singular pathway to harness the immune response and hence have associated toxicities in some patients, which may expose certain patients to experiencing immune-related adverse events, since ICIs do not consider the interactions between immune cells and complex signalling pathways in the tumour micro-environment (TME). Targeting these immune-regulatory mechanisms is thus a promising strategy in combination with ICI’s, which could lead to the development of novel immunotherapies with increased clinical efficacy and less side-effects. This is where next-generation antibodies, designed to do just that are anticipated to revolutionize the IO space.
Next generation antibody therapies are likely to be further developed to increase efficacy and decrease toxicity and their development has been driven by advances in biotechnology and the clear clinical advantages that biologics bring in multiple therapy areas. For instance, next generation antibodies have been shown to be very effective in treating autoimmune conditions and cancer, with improved target specificity, high efficacy, and favourable safety profiles.
Immunology also plays a vital role in understanding the pathogenesis of cancer, and it has therefore triggered industry interest in IO development platforms, especially when Ipilimumab became the first immune checkpoint inhibitor (ICI) monoclonal antibody (MAb) approved for cancer. IO has grown to be a significant area of biological therapy development, accounting for about one-third (33%) of all biologics currently under development, and antibodies are the most popular type of IO that is being studied and has consistently been at the top of the development pipeline. This growth was made possible by the increased focus on immuno-oncology (IO) as evidenced by the large number of agents under development, improvement in therapeutic outcomes, growing numbers of phase III trials, and the rising number of approvals. Currently, there are several forms of IOs such as fusion proteins, CAR-T therapies, oncolytic viruses, anticancer vaccines, and antibodies. The likelihood of approval (LOA) of an IO candidate in Phase I is significantly higher than the average oncology candidate LOA (12.4% vs. 5.3%). IO drugs have a notably high Phase II to Phase III transition rate of 42%, compared to 24.6% for the general cancer pipeline.
There have been 55 IOs approved to date, and due to the industry’s rapid expansion and the breadth of its development pipeline, patients will soon have access to even more IOs. This crucial stage enables the proof-of-concept efficacy and safety to be established in the intended target population. The top mechanisms of action, as sourced from the Trialtove from Citeline (Formerly Pharma Intelligence), by the number of trials for the following are:
- Immune Check-point inhibitors: over 8,000
- Immune checkpoint inhibitors: 8,433
- PD-1 antagonist: 5,663
- PD-L1 antagonist: 2,009
- T cell stimulant: 1,745
- Angiogenesis inhibitor: 1,250
- CTLA4 antagonist: 1,105
- Immunostimulant: 998
- VEGFR-2 tyrosine kinase inhibitors: 973
- DNA inhibitor: 920
- DNA synthesis inhibitor: 772
- RET tyrosine kinase inhibitors: 657
- Unidentified pharmacology: 652
- VEGFR-3 tyrosine kinase inhibitors: 630
- Most prevalent immunotherapy available: MABs
Most prevalent immunotherapy available: MABs
ICI MAbs are the most prevalent immunotherapy treatments available to patients today with melanomas and Hodgkin’s lymphoma being the most common diseases for which ICIs were initially approved. According to Citeline’s (Formerly Pharma Intelligence) Datamonitor Healthcare analysis, PD-1/PD-L1 targeted MAbs are the most popular class of NSCLC medications with 5,663 and 2,009 trial studies performed, and patient response to these types of therapy is generally low, despite immune checkpoint inhibitor trials (with a total of 8,433 studies performed) showing that they improve survival and clinical outcomes in a few indications (such as NSCLC, melanoma, and Hodgkin lymphoma). The introduction of ICIs has undoubtedly changed the game for some patients, but they are constrained by their relatively low response rate, inability to cure all cancer patients, and significant negative side effects.
Next-generation antibodies and what it could mean for the future
As of April 2022, there are 2,809 IO therapies in development. Currently, the pipeline consists of very early-stage candidates, with approximately 62 percent of all drugs in preclinical stages. Furthermore, there are 1,035 drugs in clinical trials, and 15 are awaiting approval in the pre-registration phase. On further evaluation, almost all the drugs in the preclinical stage are novel chemical or biological entities, and there are just 19 biosimilars in development, including ipilimumab, nivolumab, and pembrolizumab, and rituximab biosimilars. It is not surprising that antibodies continue to be the most prevalent type of IO in development, with 411 currently in clinical trials, given the success of MAbs in cancer therapy. The majority of these are next-generation multi-specific antibodies that focus on various antigens or epitopes on a single antigen. They can be made to target multiple cells within the TME rather than just one molecular pathway, multi-specific antibodies are extremely promising. Through a variety of mechanisms, such as T-cell costimulation, activation of innate and adaptive immune cells, inhibition of particular mutation-driven signalling pathways, concurrent blockade of two immune checkpoints, and targeting multiple antigens to increase tumour selectivity, they seek to influence tumour death. In the pipeline, bispecific antibodies (BsAbs), which have the ability to target two targets, are more common than the more complicated trispecific antibodies (TsAbs). Bispecific T cell engagers (BiTEs), which account for 40% of all BsAbs currently under development, are a significant class of BsAbs.
To more precisely target T-cell mediated cytotoxicity in the TME only and thereby reduce immune adverse events, they bind to T cells and cancer cells simultaneously. Another well-liked approach for BsAb development programmes is to focus on two checkpoint inhibitors. The first of its kind is most likely to be approved is cadonilimab, the most sophisticated bispecific checkpoint inhibitor. It has been shown to be effective in clinical trials in both PD-L1 positive and negative patients, greatly enhancing progression-free survival. New cutting-edge TsAb research programmes have been launched as a result of additional antibody research advancements. They provide even more clinical options than BsAbs because they can be designed to simultaneously target three distinct pathways or to co-localize three different antigens to create a potent immune response. New cutting-edge TsAb research programmes have been launched as a result of additional antibody research advancements. The development of bispecific and, in particular, trispecific NK cell engagers, which can be designed to use multiple targets to direct NK cells to tumours, is likely to revolutionise NK cell IO.
Multi-specific antibodies are a very promising tool because they enable simultaneous disruption of numerous cancer pathways and precise targeting of cytotoxicity. Given their precision and distinctive targeting abilities, it is likely that these medications will prove to be safer and more effective than current MAbs, and their introduction to the market could revolutionise IO. Additionally, it’s likely that as our knowledge of the intricate interactions between tumour and immune cells in the TME grows, we will discover new targets and immune signatures unique to particular cancer types and individuals. Cancer care is steadily becoming more individualised, and it’s possible that in the future, patients’ IO therapy combinations could be routinely customised based on their unique immune profiles. These potent drug classes will be crucial in personalised combination therapy since they can be modified to new target combinations in the future as the depth of research into multi-specific antibodies increases.
Antibody drugs have established themselves as essential components of cancer therapy as IO development has exploded. The introduction of ICI MAbs has been a game-changer in the industry and given patients access to urgently needed new treatment options. The next generation of cancer treatments will be brought about by developments in antibody research and development in IO, so they are not the holy grail. In order to find new therapies with improved safety and efficacy, developers in the IO space must build on the success of MAbs and advance antibody technology. Multiple pathogenic pathways in the TME can be simultaneously targeted by multi-specific antibodies, which can also better target cytotoxicity to tumour cells. They are currently the main area of development, and when they eventually hit the market, we expect them to transform and revolutionise IO.
(The author is a Consultant at Citeline, formerly Pharma Intelligence. Views expressed are personal and do not reflect the official position or policy of the FinancialExpress.com.)