Polyfunctional Orthogonal Protein Chimeras for AML
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Solution Overview
Problem
Current treatments for acute myeloid leukemia (AML) are inadequate, particularly for older patients who cannot undergo intensive chemotherapy, with a median survival of only 5 to 10 months and existing therapies like Gemtuzumab ozogamicin and BiTEs showing limited efficacy and bioavailability issues.
Innovation Solution
Development of engineered polyspecific or polyfunctional proteins using non-naturally occurring polypeptide domains with 1-5 alpha helices connected by amino acid linkers and an IgG2 hinge domain, which form covalent disulfide bonds for stability and engage the body's complement system, allowing for enhanced tumor killing by targeting CD33+ cells with NK and T-cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Gemtuzumab ozogamicin is used as monotherapy, then CD33 targeting is achieved, but treatment efficacy is insufficient and does not improve outcomes
Solution Approach 1:
The patent combines multiple functional domains into a single engineered protein: an antigen-binding fragment targeting CD33, a non-naturally occurring polypeptide domain for dimerization and stability, and an IgG2 hinge domain for complement system engagement. This merging of functions into one molecule achieves reliable tumor cell killing without requiring complex combination therapies.
Solution Approach 2:
The engineered protein performs multiple functions simultaneously: it binds to CD33 on AML cells for targeted recognition, forms stable dimers through covalent disulfide bonds for enhanced stability and reduced immunogenicity, and engages the complement system via the IgG2 hinge domain for cytotoxic activity. This multi-functionality in a single molecule resolves the contradiction between efficacy and therapy complexity.
2Reliability
If BiTEs are used to engage T-cells, then CD33+ AML targeting is achieved, but bioavailability is extremely low requiring continuous injection
Solution Approach 1:
The patent changes the structural parameters of the therapeutic protein by incorporating an IgG2 hinge domain instead of relying solely on BiTE structure. This modification enables complement system engagement and achieves prolonged circulation and target engagement without requiring continuous injection, thereby improving bioavailability duration while maintaining reliable target engagement.
3Adaptability or versatility
If fusion proteins are used for polyfunctional proteins, then multiple targets can be engaged, but steric inhibition of engaging sites occurs reducing functionality
Solution Approach 1:
The patent segments the protein into distinct functional domains connected by linkers: an antigen-binding fragment, a non-naturally occurring polypeptide domain with alpha helices for dimerization, and an IgG2 hinge domain. This segmentation allows each domain to perform its function independently without steric inhibition, maintaining reliable binding functionality while achieving multi-target engagement capability.
Solution Approach 2:
The non-naturally occurring polypeptide domain acts as an intermediary between the antigen-binding fragment and the IgG2 hinge domain. This intermediary domain with 1-5 alpha helices connected by amino acid linkers provides a flexible connection that prevents steric inhibition while enabling covalent dimerization through disulfide bonds, thus preserving binding functionality.
4Reliability
If NK cells are used for cytotoxic response, then tumor killing is enhanced, but AML suppresses NK maturation and function reducing effectiveness
Solution Approach 1:
The engineered protein self-activates the complement system through its IgG2 hinge domain without requiring external activation signals that AML might suppress. The protein's structure inherently enables complement engagement, allowing it to overcome AML-mediated immune suppression and maintain reliable cytotoxic activity against tumor cells.
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
These engineered proteins demonstrate improved stability, reduced immunogenicity, and better pharmacokinetics, enabling effective targeting and cytotoxicity against AML cells, potentially offering a more effective treatment option for AML.
Implementation Method 1
non-naturally occurring polypeptide domain comprising 1-5 alpha helices connected by amino acid linkers
Implementation Method 2
engage the body's complement system, allowing for enhanced tumor killing
Data Source
AI summary
Disclosed herein are engineered heterodimer or heterotrimer proteins which use a non-naturally occurring polypeptide domain comprising 1-5 alpha helices connected by amino acid linkers and an IgG2 hinge domain either alone or in conjunction with an IgG2 Fc domain. The heterodimer and heterodimer proteins can further comprise an antigen-binding fragment that binds a lineage-specific cell-surface antigen, a polypeptide that binds to a molecule expressed on an immune cell (e.g., natural killer cell) and/or a polypeptide that binds to a molecule expressed on another type of immune cell (e.g., T cells). Also disclosed herein are nucleic acids encoding the proteins, vectors comprising the nucleic acids, compositions, and methods of treatment.