ROR1-Specific VNAR Binding Molecules for Targeted Cancer Therapy
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Solution Overview
Problem
Current therapies for cancer, particularly those targeting ROR1, face challenges in specificity and efficacy due to the general lack of ROR1 expression in normal adult tissues but its re-expression in various cancer types.
Innovation Solution
Development of ROR1-specific antigen binding molecules, such as immunoglobulin-like shark variable novel antigen receptors (VNARs), which are designed to selectively bind to ROR1 with high affinity, thereby facilitating targeted therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies or therapy molecules are used to target ROR1, then cancer treatment can be initiated, but specificity and efficacy are compromised due to ROR1's re-expression in cancer types and lack of expression in normal adult tissues
Solution Approach 1:
The patent applies parameter changes by modifying the binding interface of the antigen binding molecule to specifically recognize a conserved epitope on ROR1 that is present in cancer cells but absent or low-expression in normal adult tissues. This selective epitope recognition changes the binding parameters to achieve high specificity while maintaining efficacy across different cancer types that re-express ROR1.
Solution Approach 2:
The patent uses a shark-derived VNAR (variable novel antigen receptor) that copies the successful binding mechanism of natural shark antibodies against ROR1. The VNAR is derived from shark immunoglobulin-like proteins that naturally bind ROR1 with high affinity, effectively copying a proven binding interface that works across human and murine ROR1 variants, thereby achieving both specificity and broad efficacy.
2Productivity
If ROR1-targeted therapy is developed, then cancer cells expressing ROR1 can be targeted, but off-target effects may occur due to ROR1 expression in neural crest cells and embryonic tissues
Solution Approach 1:
The patent applies local quality by designing the antigen binding molecule to recognize a specific local epitope on the ROR1 protein that is selectively expressed in cancer cells. The binding interface is optimized to distinguish between ROR1 in different contexts (embryonic vs. adult vs. cancer), allowing anti-tumor activity in ROR1-expressing cancers while minimizing effects on tissues where ROR1 is normally expressed during development.
Solution Approach 2:
The patent uses an Fc-engineered or Fc-fused platform as an intermediary to deliver the VNAR to tumor cells. The Fc portion can be engineered to enhance tumor cell uptake while avoiding binding to normal tissues, thereby mediating the interaction between the VNAR and ROR1 in a way that maximizes anti-tumor activity and minimizes off-target effects in neural crest and embryonic tissues.
3Strength
If high affinity binding to ROR1 is achieved, then tumor cell killing is enhanced, but binding to ROR2 or other similar proteins may occur reducing selectivity
Solution Approach 1:
The patent applies asymmetry by designing an asymmetric binding interface in the VNAR that specifically accommodates the unique structural features of ROR1. The complementarity determining regions are configured with asymmetric contact patterns that match the asymmetric epitope on ROR1, creating high affinity binding that is structurally incompatible with ROR2 and other related proteins, thus maintaining selectivity despite high affinity.
Solution Approach 2:
The patent segments the antigen binding molecule into distinct functional regions: the VNAR domain that provides specific ROR1 recognition through its complementarity determining regions, and the Fc or fusion domain that provides effector functions. This segmentation allows the VNAR to be optimized for specific high-affinity binding to ROR1 while the Fc portion handles the effector functions, preventing cross-reactivity with ROR2 through functional separation.
Data Source
AI summary
The present invention relates to receptor tyrosine kinase-like orphan receptor 1 (ROR1) specific antigen binding molecules and associated fusion proteins and conjugates. In a further aspect, the present invention relates to conjugated immunoglobulin-like shark variable novel antigen receptors (VNARs).