Anti-CD33 Single-Domain Antibody Constructs for AML
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Solution Overview
Problem
Current therapies for acute myeloid leukemia (AML) often lead to remissions, but almost all patients eventually relapse, highlighting the need for an effective immunotherapeutic agent.
Innovation Solution
Development of anti-CD33 single-domain antibodies (sdAbs) and constructs, including chimeric receptors, immune effector cell engagers, and immunoconjugates, engineered to specifically target CD33, a protein expressed on AML cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If conventional 4-chain antibodies are used to target CD33 on AML cells, then antigen binding capability is achieved, but the molecular size and structural complexity increase
Solution Approach 1:
The patent extracts only the essential antigen-binding variable domain (VHH) from the complete 4-chain antibody structure. This single-domain antibody retains the ability to bind CD33 antigen while eliminating the complex light chain and constant region structures, achieving simplified design without sacrificing binding function
Solution Approach 2:
The patent segments the antibody into independent single-domain units (VHH) that can function autonomously. Each VHH domain is a separate, functional unit capable of antigen binding, allowing modular construction and reduced overall complexity compared to interconnected 4-chain structures
2Device complexity
If single-domain antibodies are used to target CD33, then structural simplicity and reduced molecular weight are achieved, but potential reduced stability compared to conventional antibodies may occur
Solution Approach 1:
The patent modifies the VHH domain structure by introducing stabilizing mutations and optimizing amino acid sequences. These parameter changes in the protein structure enhance the thermal and chemical stability of the single-domain antibody, compensating for the potential instability inherent in simplified structures
3Productivity
If conventional CAR-T therapy is used to treat AML, then anti-tumor response is activated, but relapse occurs in almost all patients indicating insufficient long-term efficacy
Solution Approach 1:
The patent uses single-domain antibody sequences (particularly VHH from camelid antibodies) as simplified copies of conventional antibody variable regions. These VHH-based CAR constructs replicate the antigen recognition function while offering improved stability and reduced immunogenicity, potentially leading to better long-term therapeutic outcomes
Solution Approach 2:
The patent modifies CAR construct parameters by replacing conventional scFv with VHH domains, changing the structural and functional parameters of the chimeric antigen receptor. This parameter change improves the overall performance and durability of the immunotherapy approach
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 anti-CD33 constructs demonstrate specific binding to CD33, potentially leading to targeted anti-tumor responses and improved treatment outcomes for AML patients.
Implementation Method 1
an anti-CD33 construct comprising an single domain antibody ("sdAb") moiety that specifically binds to CD33
Data Source
AI summary
The present application provides single-domain antibodies targeting CD33 and constructs thereof, including chimeric receptors, immune effector cell engagers and immunoconjugates. Further provided are engineered immune cells (such as T cells) comprising an anti-CD33 chimeric receptor and optionally a second chimeric receptor targeting a second antigen or epitope. Pharmaceutical compositions, kits and methods of treating cancer are also provided.