Cartilage-Anchored ISVD Polypeptides for Osteoarthritis Retention
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Solution Overview
Problem
Current treatments for osteoarthritis (OA) lack effective disease-modifying anti-osteoarthritic drugs (DMOADs) that can inhibit structural deterioration of joints and are associated with significant side effects, and existing drug delivery methods struggle with rapid clearance from articular cartilage, necessitating frequent and painful injections.
Innovation Solution
Development of polypeptides comprising immunoglobulin single variable domains (ISVDs) that specifically bind ADAMTS5, MMP13, and Aggrecan, combined with cartilage anchoring moieties, to provide prolonged retention and inhibit protease activity in the joint, reducing the need for frequent injections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for osteoarthritis are used, then symptom management is provided, but structural deterioration of joints is not inhibited and significant side effects occur
Solution Approach 1:
The invention divides the therapeutic approach into multiple specific components: polypeptides targeting ADAMTS5, polypeptides targeting MMP13, and polypeptides targeting Aggrecan. This segmentation allows selective inhibition of specific proteases responsible for cartilage degradation without the broad-spectrum effects that cause side effects in conventional treatments
Solution Approach 2:
The patent uses polypeptides as intermediary molecules that specifically bind to and inhibit the activity of ADAMTS5, MMP13, and Aggrecan. These polypeptides act as mediators between the therapeutic goal (inhibiting cartilage degradation) and the target proteases, providing selective and controllable inhibition without the harmful effects of non-specific treatments
2Reliability
If protease inhibitors are administered, then cartilage degradation is inhibited, but the drugs are not retained in the joint for extended periods
Solution Approach 1:
The invention merges two distinct functions into a single polypeptide molecule: (1) the protease inhibitory function (binding to ADAMTS5, MMP13, or Aggrecan) and (2) the cartilage anchoring function (binding to Aggrecan or Collagen II). This merging ensures that the inhibitory action and prolonged retention occur simultaneously at the same location
Solution Approach 2:
The polypeptides are designed to bind to cartilage matrix components (Aggrecan or Collagen II), allowing them to anchor themselves to the cartilage tissue. This self-anchoring mechanism ensures prolonged retention in the joint without requiring external delivery systems or frequent re-administration
3Reliability
If multiple protease targets are addressed, then comprehensive inhibition of cartilage degradation is achieved, but polypeptide complexity increases
Solution Approach 1:
The invention segments the therapeutic approach into three distinct polypeptide types, each with a specific target (ADAMTS5, MMP13, or Aggrecan). This segmentation allows each polypeptide to be relatively simple in structure while collectively providing comprehensive coverage of all major proteolytic pathways involved in cartilage degradation
Solution Approach 2:
The polypeptides are designed with universal features that enable them to bind to multiple targets or perform multiple functions. For example, some polypeptides can bind to both proteases and cartilage matrix components, providing both inhibition and anchoring functions within a single molecular structure
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 polypeptides effectively inhibit ADAMTS5 and MMP13, remain stable in the joint for extended periods, and demonstrate improved safety and efficacy in various OA models, potentially offering a safer and more convenient treatment option for OA.
Implementation Method 1
polypeptides comprising immunoglobulin single variable domains (ISVDs) that specifically bind ADAMTS5, MMP13, and Aggrecan
Data Source
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AI summary
The present invention relates to polypeptides binding Aggrecan as well as ADAMTS5 and/or MMP13, more in particular to polypeptides that comprise or essentially consist of immunoglobulins binding Aggrecan as well as immunoglobulins binding ADAMTS5 and/or immunoglobulins binding MMP13 (also referred to herein as "polypeptides of the invention", and "immunoglobulin(s) of the invention", respectively). The invention also relates to constructs comprising such immunoglobulins, such as immunoglobulin single variable domains (ISVDs) or polypeptides as well as nucleic acids encoding such immunoglobulins or polypeptides (also referred to herein as "nucleic acid(s) of the invention"; to methods for preparing such immunoglobulins, polypeptides and constructs; to host cells expressing or capable of expressing such immunoglobulins or polypeptides; to compositions, and in particular to pharmaceutical compositions, that comprise such immunoglobulins, polypeptides, constructs, nucleic acids and/or host cells; and to uses of immunoglobulins, polypeptides, constructs, nucleic acids, host cells and/or compositions, in particular for prophylactic and/or therapeutic purposes, such as the prophylactic and/or therapeutic purposes mentioned herein. Other aspects, embodiments, advantages and applications of the invention will become clear from the further description herein.