DKK1/HLA-A2 Binding Molecules for Pancreatic Cancer
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Solution Overview
Problem
Current immunotherapies, such as immune checkpoint blockade and CAR-T cell therapy, have shown limited effectiveness in treating pancreatic cancer and non-small-cell lung cancer, with challenges including targeting tumor antigens, infiltrating tumor microenvironments, and reducing toxicities.
Innovation Solution
Development of antigen binding molecules, including RNAi, peptides, CAR T cells, and bi-specific antibodies, that specifically bind to the Dickkopf-1 (DKK1) peptide P20 in the context of HLA-A2, which are designed to target and treat pancreatic cancer and non-small-cell lung cancer by exploiting the differential expression of DKK1 in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint blockade (ICB) is used to treat pancreatic cancer, then the treatment approach aligns with successful therapies for melanoma and lung cancer, but the therapy shows almost entirely refractory results with no significant response
Solution Approach 1:
The patent applies local quality by targeting a specific tumor antigen (DKK1) that is differentially expressed in pancreatic cancer and NSCLC cells rather than using a universal checkpoint blockade approach. The antigen binding molecules are designed to specifically recognize DKK1 peptide P20 in the context of HLA-A2, providing tumor-specific targeting that adapts to the unique characteristics of these cancer types.
Solution Approach 2:
The patent employs parameter changes by shifting from a general immune checkpoint blockade mechanism to a targeted approach against DKK1 antigen. The invention identifies and targets specific molecular parameters (DKK1 peptide sequence, HLA-A2 binding affinity) that differ between tumor types, thereby adapting the therapy to achieve effectiveness in pancreatic cancer and NSCLC where conventional ICB fails.
2Force
If CAR-T cell therapy is used to target solid tumors, then the approach leverages potent immune cell engagement, but the therapy fails to improve survival and demonstrate significant response due to challenges in antigen targeting, tumor microenvironment infiltration, and toxicity reduction
Solution Approach 1:
The patent extracts the essential antigen-targeting function from the complex CAR-T cell structure by using antigen binding molecules (antibodies, antibody fragments, or other binding agents) that specifically bind to DKK1 peptide P20. This simplifies the therapeutic approach by separating the antigen recognition function from the cytotoxic effector function, allowing the use of various delivery platforms beyond CAR-T cells while maintaining specific tumor targeting.
Solution Approach 2:
The patent introduces antigen binding molecules as intermediaries between the immune system and tumor cells. These molecules serve as mediators that specifically recognize DKK1 on tumor cells and can engage immune effector mechanisms (such as ADC, CDC, or T cell recruitment) without requiring direct CAR-T cell engineering, thereby reducing complexity while maintaining therapeutic force.
3Adaptability or versatility
If conventional immunotherapies are used for non-small-cell lung cancer, then the treatment provides standard of care options, but the response rates remain low (≈20%) and many responders eventually develop resistance
Solution Approach 1:
The patent segments the tumor targeting approach by identifying and targeting a specific antigen (DKK1) that is differentially expressed in NSCLC cells. Rather than relying on universal checkpoint inhibitors, the invention divides the therapeutic strategy into tumor-specific antigen recognition (DKK1-P20/HLA-A2) followed by immune effector engagement, thereby adapting conventional immunotherapy to achieve higher and more durable response rates in NSCLC.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These molecules demonstrate specific binding and cytotoxicity towards cancer cells, inducing apoptosis and suppressing tumor progression, offering a potential new approach for treating these aggressive cancers.
Implementation Method 1
antigen binding molecules that specifically bind to Dickkpf-1 (DKK1) peptide P20 in the context of HLA-A2
Implementation Method 2
These molecules demonstrate specific binding and cytotoxicity towards cancer cells, inducing apoptosis and suppressing tumor progression
Data Source
AI summary
Disclosed are antigen binding molecules that bind to Dickkopf-1 (DKK1) P20 peptide in the context of MHC-HLA-A2 (i.e., a DKK1-A2 complex). Such antigen binding molecules can by antibodies, antibody fragments, bi-specific antibodies, immunotoxins or the chimeric antigen receptor portion of a chimeric antigen receptor T cell. Also disclosed herein are methods of using said antigen binding molecules for the treatment of cancer.