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.

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.