4-1BBL Ectodomain Polypeptides for Targeted Cancer Immunotherapy
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Solution Overview
Problem
Current strategies for activating 4-1BB in cancer immunotherapy face challenges such as severe side effects, systemic toxicity, and inefficient tumor targeting, often relying on non-human sequences that trigger immune responses and are difficult to predict, with existing approaches failing to effectively cluster 4-1BB receptors for potent costimulatory activity.
Innovation Solution
Development of costimulatory polypeptides comprising a 4-1BBL ectodomain with a trimerization domain and a minimal TNF Homology Domain, designed to bind to 4-1BB on the surface of immune cells, triggering immune cell stimulation without using non-human sequences, and potentially encoded in oncolytic viruses for targeted delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-human sequences are used to activate 4-1BB, then costimulatory activity is achieved, but severe side effects and systemic toxicity occur
Solution Approach 1:
The patent uses humanized monoclonal antibodies that copy the natural ligand structure (4-1BBL) using human sequences instead of non-human sequences. This allows the antibody to bind to 4-1BB receptors and provide costimulatory activity while avoiding immune recognition as foreign, thereby reducing side effects and toxicity.
Solution Approach 2:
The patent modifies the sequence parameters of the antibody by using humanized sequences with specific amino acid substitutions (e.g., at positions 51, 90-240) compared to the natural ligand. This changes the binding parameters to maintain affinity for 4-1BB while improving biocompatibility and reducing harmful immune responses.
2Reliability
If non-human sequences are used for 4-1BB activation, then costimulatory effect is achieved, but immune responses are triggered
Solution Approach 1:
The patent creates humanized antibodies that copy the structural and functional parameters of the natural 4-1BBL ligand using human gene sequences. This copying approach ensures the antibody is recognized as self by the immune system, preventing harmful immune responses while maintaining the costimulatory effect through binding to 4-1BB receptors.
3Device complexity
If monomeric 4-1BBL is used, then simplicity is maintained, but very low activity is observed
Solution Approach 1:
The patent combines multiple 4-1BBL ectodomain units into a single polypeptide structure through fusion. This merging of functional units creates a multimeric protein that maintains the simplicity of a single molecular entity while achieving high costimulatory activity through the combined binding capability of multiple units.
Solution Approach 2:
The patent creates a composite protein structure by fusing the 4-1BBL ectodomain with other functional domains (such as Fc regions or other binding domains). This composite approach maintains the simplicity of a single protein molecule while enhancing activity through the synergistic combination of different functional elements.
4Ease of manufacture
If existing 4-1BB activation strategies are used, then treatment approaches are established, but tumor targeting is inefficient
Solution Approach 1:
The patent introduces tumor-specificity through local quality modifications, such as combining the 4-1BBL ectodomain with tumor-targeting domains or using antibody formats that preferentially bind to tumor-associated antigens. This allows the costimulatory activity to be localized to tumor sites while maintaining the established mechanism of 4-1BB activation.
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 achieve effective immune cell stimulation with reduced toxicity and improved tumor specificity, enhancing anti-tumor responses by mimicking the natural 4-1BBL ligand and avoiding adverse immune reactions, thus providing a safer and more effective cancer treatment.
Implementation Method 1
the polypeptide binds to 4-1BB on the surface of a 4-1BB expressing cell and thus triggers 4-1BB-mediated immune cell stimulation
Implementation Method 2
oligomerization of tumor necrosis family ligands such as CD40L is required for triggering of signaling pathways
Data Source
AI summary
The present invention generally relates to the field of immunomodulation and provides various costimulatory polypeptides comprising at least one 4-1BBL ectodomain comprising a (core) minimal TNF Homology Domain. Further provided are vectors and oncolytic viruses expressing the 4-1BBL ectodomain and methods for producing the same. Additionally provided are 5 methods and uses for obtaining and optionally purifying the inherently oligomerizing 4-1BBL ectodomain polypeptides and associated oncolytic viruses for highly targeted cancer treatment, including the treatment of tumors. Finally, there are provided kits and uses of the polypeptides and vectors as disclosed.