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• Antibody-based immune checkpoint inhibitors (ICIs) have fundamentally changed the way we treat cancer. However, there are limitations to their benefits with most cancer patients still not responding to treatment or eventually develop resistance or relapse following initial response.
• PD-1 blockade immunotherapy, which is the leading ICI available, shows therapeutic response in only about 20–30% of all cancer patients. Even among those who initially respond to treatment, nearly half develop drug resistance and experience relapse over time.
Various Mechanisms of Resistance to Anti-PD-1 Immune Checkpoint Inhibitors
Tumor cells can induce ICI (immune checkpoint inhibitor) resistance or unresponsiveness through various mechanisms. These are broadly classified into three categories: (1) Immune-inflamed TME: Characterized by PD-1 overexpression or activation of other immune checkpoints, leading to T cell exhaustion despite immune cell infiltration. (2) Immune-excluded TME: Immune cells are present but fail to infiltrate the tumor microenvironment (TME), resulting in reduced functionality. (3) Immune-desert TME: Characterized by a complete lack of immune infiltration or impaired antigen presentation, leading to immune ignorance.
Improved safety and efficacy through targeted delivery of cytokines using antibodies.
• Cytokines have potential as anticancer agents due to their ability to activate and proliferate immune cells against tumors. However, systemic administration can lead to indiscriminate immune activation, causing severe toxicity. They are rapidly cleared from the bloodstream (half-life of 30 minutes to 2 hours), making sustained therapeutic effects difficult to achieve.
• When cytokines are conjugated with antibodies, they can be precisely delivered to the tumor microenvironment, which helps reduce toxicity associated with systemic administration.
• Additionally, antibody-conjugated cytokines show significantly increased blood retention, allowing them to exert anticancer effects for a longer period.
Securing Differentiated Cytokines through Advanced Discovery Technology and Systematic Evaluation
• Based on our advanced antibody discovery platform, we have secured approximately 1,000 cytokine gene-modified sequences. Among them, we have identified cytokine variants with outstanding efficacy, safety, and productivity, and have fused them into various bispecific antibodies, leading to the development of a diverse Multi-AbKine pipeline.
Cytokine Variant Gene Identification:
~1,000 variants
✓ Identification of key amino acids
✓ Application of random mutation
✓ Modulation of receptor binding affinity
In vitro Evaluation:
~50 variants
✓ Ensuring high manufacturability
✓ Tuning of receptor binding
✓ Functional evaluation after antibody fusion
In vivo Evaluation:
~10–20 variants
✓ Assessment of anti-tumor efficacy and safety
✓ Comparison with competitor substances
Candidate Molecules:
~1-3 variants
✓ Identification of optimized cytokines
