Immune checkpoint inhibitors (ICIs) have provided an unprecedented duration of response and disease-free survival outcomes in cancer therapy, a feat that has enabled their integration as the backbone treatment-of-choice in many cancer types.
Using ICIs in order to lift the biological ‘brakes’ that cancer cells exploit to avoid immune clearance was a major breakthrough in immuno-oncology (IO). However, despite the value of ICIs in fighting cancer, there are certain limitations to ICI therapy. Heavy toxicities and immune-related adverse events related to the use of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies, such as Bristol-Myers Squibb’s Yervoy (ipilimumab) and AstraZeneca’s tremelimumab, have been a major drawback, ultimately limiting the therapeutic potential for the drug class. Anti-programmed cell death 1 (PD-1)- and anti-programmed cell death ligand 1 (PD-L1)-targeting drugs are comparatively well-tolerated; however, acquired drug resistance and lack of response in immunosuppressive or “cold” cancer types are some of the factors that reduce the future expansion of the drug class.
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In order to overcome some of these hurdles, different types of IO agents such as chimeric antigen receptor T (CAR-T) cell therapies and therapeutic cancer vaccines are being trialled in combination with ICIs. Compared to these novel combination approaches, bi-specific monoclonal antibodies with dual checkpoint activities are considered as a more practical and versatile approach. In the preclinical models and early-phase clinical trials, bi-specific immune checkpoint modulator antibodies showed superior target binding affinities and inhibitory activities compared to single-target ICIs and lacked some of the unwanted adverse events and toxicity burden. A few key bi-specific drug candidates are moving down the pipeline in multiple tumour types and hold significant clinical and commercial value for the future of IO therapies.
Bi-specific checkpoint modulator antibodies that are in early- to mid-stage development include Alphamab Oncology’s KN-046 and Akeso Biopharma’s AK-104, both designed to target CTLA-4 and PD-(L)1. These agents have high specificity to tumours that overexpress both of the targets, and early studies have demonstrated that they have substantially reduced toxicities compared to what anti-CTLA-4 therapies cause as monotherapies or in combination with anti-PD-(L)1 therapy. Alphamab Oncology is currently conducting Phase I/II trials for KN-046 in non-small cell lung cancer (NSCLC), oesophagal squamous cell carcinoma (ESCC), and triple-negative breast cancer (TNBC), although not in any of the seven major markets (7MM: US, France, Germany, Italy, Spain, UK, Japan). Akeso Biopharma reported 24% overall response and 44% disease control rate obtained for AK-104 in subjects with advanced solid tumours in a Phase I trial. Although the efficacy data are nothing more than encouraging at the moment, from the safety standpoint, the Phase I study suggests an improved tolerance to AK-104 compared to a combination of anti-PD-1 and anti-CTLA-4 therapies. In addition to the clinical trials in China and Australia, the company aims to initiate a clinical trial in the US to investigate AK-104’s use in the late-line treatment of advanced cervical cancer, which provides a significant opportunity for AK-104 to become the first-in-class bi-specific checkpoint-targeting drug in any of the 7MM.
Drug developers are investigating ways to overcome anti-PD-(L)1 resistance by targeting novel checkpoints and one of the most promising novel targets is lymphocyte activation gene 3 (LAG-3). MacroGenics’ MGD-013 is a bi-specific antibody that can bind to LAG-3 and PD-1 concurrently and is claimed to have a potentiating effect on the anti-PD-1 activity. MGD-013, one of two bi-specific checkpoint modulators in Macrogenics’ portfolio, is in Phase I development for solid tumours. Table 1 summarizes the key bi-specific immune checkpoint modulator antibodies currently in development and GlobalData continues to monitor their progress with interest.
ICIs have earned a prominent place in the treatment of cancer due to significant improvements in survival outcomes. Despite their substantial therapeutic value, certain mechanistic features of anti-CTLA-4 antibodies hinder their overall safety profile, and for anti-PD-(L)1 antibody drug resistance and lack of response in certain patients is an ongoing concern. According to key opinion leaders (KOLs) interviewed by GlobalData, bi-specific antibodies that can target multiple immune checkpoints are a robust therapeutic approach, mainly because of the improved inhibitory (and co-stimulatory) activity with lower levels of toxicities compared to single-target checkpoint inhibitors. However, physicians share concerns of overstimulation of the immune system via two potent checkpoint-controlled pathways, which carries the risk of triggering complex autoimmune-like adverse events. Overall, bi-specific immune checkpoint modulator antibodies could be refined further to replace or complement existing cancer therapies and help physicians and researchers understand cancer immunity even more.
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