HER2 Binding Polypeptides for Tumor Penetration and Specificity
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Solution Overview
Problem
Current antibody therapies for cancers with HER2 overexpression face challenges such as limited penetration, reduced vascular permeability, cross-reactivity with normal tissues, heterogeneous tumor uptake, increased metabolism, and immune-mediated complications, leading to reduced efficacy and significant side effects.
Innovation Solution
Development of a novel HER2 binding polypeptide with specific amino acid sequences that exhibit improved binding affinity, reduced non-specific binding, enhanced stability, and lower antigenicity, allowing for effective targeting and treatment of HER2-positive cancers with improved biodistribution and reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antibody therapies are used for HER2-positive cancers, then therapeutic targeting is achieved, but penetration into tumors is limited and vascular permeability is reduced
Solution Approach 1:
The patent changes the molecular parameters of the therapeutic agent by using small polypeptides (e.g., Affibody molecules with 58 amino acids) instead of large antibodies (150 kDa). This size reduction fundamentally alters penetration speed and tissue distribution while maintaining target binding capability through engineered affinity for HER2
Solution Approach 2:
The patent employs short-lived small polypeptide molecules that can be rapidly cleared and re-administered, enabling repeated dosing with different radiolabels or therapeutic agents. These short-lived molecules provide flexible, disposable targeting vectors that avoid the accumulation and immunogenicity issues of long-lived antibodies
2Reliability
If current antibody therapies are used, then HER2 targeting is achieved, but cross-reactivity with normal tissues occurs
Solution Approach 1:
The patent applies local quality by engineering polypeptides with highly specific binding characteristics tailored for HER2. The Affibody molecules are designed with specific amino acid sequences that recognize unique epitopes on HER2, creating localized high-affinity binding at the target site while minimizing off-target interactions through optimized binding interfaces
Solution Approach 2:
The patent creates simplified copies of antibody binding functionality using small polypeptide structures. These polypeptide copies mimic the target recognition capability of full antibodies but with reduced size and improved tissue penetration, effectively copying the essential therapeutic function while eliminating size-related limitations
3Reliability
If current antibody therapies are used, then treatment is achieved, but heterogeneous tumor uptake occurs
Solution Approach 1:
The patent segments the large antibody molecule into smaller polypeptide units that can more uniformly distribute within tumor tissue. The small size (58 amino acids) allows these segmented molecules to penetrate heterogeneous tumor environments more evenly, achieving more uniform radiolabel distribution and consistent therapeutic delivery across different tumor regions
4Reliability
If current antibody therapies are used, then HER2 binding is achieved, but metabolism is increased and immune-mediated complications occur
Solution Approach 1:
The patent uses short-lived small polypeptide molecules that are rapidly cleared from the body through renal filtration. This short half-life reduces metabolic burden and minimizes immune-mediated complications, allowing repeated administration cycles with different radiolabels or therapeutic payloads while maintaining effective HER2 targeting during the brief circulation period
Data Source
AI summary
HER2 binding polypeptides comprising the amino acid sequence EX1 RNAYWEIA LLPNLTNQQK RAFIRKLYDD PSQSSELLX2E AKKLNDSQ wherein X1 in position 2 is M, I or L, and X2 in position 39 is S or C (SEQ ID NO:1) are disclosed. Moreover, such peptides comprising a chelating environment are disclosed. Also radiolabeled polypeptides formed by the peptides comprising a chelating environment and radionuclides are disclosed. Furthermore, methods of in vivo imaging of the body of a mammalian subject having or suspected of having a cancer characterized by overexpression of HER2 comprising administration of such a radiolabeled polypeptide followed by obtainment of an image of the body using a medical imaging instrument and also methods of treating such cancer are disclosed. Furthermore, the use of such a radiolabeled polypeptide in diagnosis and treatment of cancer characterized by overexpression of HER2. Nucleic acids encoding the polypeptides, expression vectors comprising the nucleic acids and host cells comprising the expression vectors are also disclosed.