HER2-Targeting Cyclic Peptides for HER2-Low Cancers
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Solution Overview
Problem
Current HER2-targeted therapies are ineffective for breast cancers with low levels of HER2 expression and heterogeneity, leading to challenges in antigen engagement and dose-limiting toxicities, limiting treatment options for approximately 50% of breast cancer patients.
Innovation Solution
Development of cyclic peptides with high affinity for HER2, conjugated to imaging agents, chelating agents, or cytotoxic drugs, allowing for targeted imaging and treatment of HER2-implicated cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies and TKIs are used for HER2-targeted therapy, then treatment effectiveness is improved for HER2-amplified breast cancers, but treatment fails for approximately 50% of breast cancers with low HER2 expression due to insufficient antigen engagement
Solution Approach 1:
The patent changes the binding affinity parameter of the targeting agent by using cyclic peptides with KD values of 1000 nM or less (including 100-500 nM ranges), representing a significant increase in affinity compared to conventional monoclonal antibodies. This parameter change enables effective target engagement even at low antigen densities characteristic of HER2-low breast cancers, thereby extending treatment applicability to the 50% of patients previously untreated.
2Ease of manufacture
If antibody-drug conjugates are used to deliver cytotoxic payloads, then targeted treatment is achieved, but dose-limiting toxicities occur due to payload toxicity and on-target activity in normal tissues
Solution Approach 1:
The patent introduces cyclic peptides as high-affinity intermediaries that mediate between the cytotoxic payload and the HER2 target. The cyclic peptide's superior binding affinity (KD ≤ 1000 nM) compared to conventional antibodies enables more efficient target engagement and selective accumulation at the tumor site, thereby improving the therapeutic window and reducing dose-limiting toxicities while maintaining targeted delivery capability.
3Reliability
If conventional monoclonal antibodies are used for HER2 targeting, then treatment is effective for HER2-amplified cancers, but antigen engagement is insufficient in HER2-low tumors due to lower antigen density and cellular heterogeneity
Solution Approach 1:
The patent changes the binding affinity parameter by employing cyclic peptides with KD values of 1000 nM or less (including 100-500 nM ranges), representing a significant increase in affinity compared to conventional monoclonal antibodies. This parameter change enables effective target engagement even at low antigen densities characteristic of HER2-low breast cancers, thereby extending treatment applicability to the 50% of patients previously untreated.
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
The cyclic peptides exhibit strong binding to HER2 with a dissociation constant of 1000 nM or less, providing effective tumor retention and enabling targeted imaging and treatment of HER2-related diseases.
Implementation Method 1
at least one cyclized peptide that binds to human epidermal growth factor receptor 2 (HER2) with a dissociation constant (KD) of about 1000 nM or less
Data Source
AI summary
Described herein are cyclic peptides targeting human epidermal growth factor receptor 2 (HER2), and their incorporation into compounds for radioligand imaging and therapies, as well as methods and/or uses of such compounds for the imaging, treatment and/or prevention of HER2-implicated diseases and disorders (e.g., cancer).