Humanized Antigen Binding Receptors for Tumor Targeting
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Solution Overview
Problem
Adoptive T cell therapy (ACT) faces limitations due to treatment-related toxicities, specificity issues, and long-term survival of engineered T cells, which can lead to off-target effects and damage to healthy tissues, and existing approaches using molecular switches or tagged antibodies may elicit immune responses and increase production complexity.
Innovation Solution
Development of humanized antigen binding receptors with an anchoring transmembrane domain and an extracellular domain comprising specific antigen binding moieties, which are stable and highly expressed in transduced cells, and paired with antibodies containing a mutated Fc domain to enhance specificity and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If engineered T cells are used in ACT to treat cancer, then tumor targeting capability is improved, but treatment-related toxicities and off-target effects increase
Solution Approach 1:
The patent introduces an adaptor molecule comprising a modified Fc domain that acts as an intermediary between the tumor-targeting antibody and the T cell. The T cell expresses a chimeric antigen receptor (CAR) that binds to the modified Fc domain rather than directly to the tumor antigen. This intermediary system allows the T cell to be recruited to tumor cells via antibody-Fc receptor interactions while reducing direct engagement with tumor antigens, thereby improving targeting capability while reducing off-target effects and treatment-related toxicities.
2Productivity
If T cells are engineered with high proliferation capacity for long-term survival, then tumor lysis efficiency is improved, but persistence of uncontrolled T cell response increases causing damage to healthy tissue
Solution Approach 1:
The patent employs a dynamic control system where the adaptor molecule (modified Fc domain) serves as a switchable intermediary. The T cell's activation and proliferation are dynamically controlled by the presence and concentration of the adaptor molecule. When the adaptor molecule is present at appropriate levels, T cells are activated and proliferate to achieve high tumor lysis efficiency. When the adaptor molecule is removed or its concentration is reduced, T cell activation is downregulated, preventing uncontrolled proliferation and damage to healthy tissue. This dynamic on/off control mechanism resolves the contradiction between maintaining high productivity and preventing harmful side effects.
3Measurement precision
If molecular switches or tagged antibodies are introduced to guide T cell specificity, then targeting precision is improved, but production complexity and immune response risk increase
Solution Approach 1:
The patent utilizes the universal Fc domain of antibodies, which naturally binds to Fc receptors on immune cells, as the basis for the adaptor molecule. By introducing a modified Fc domain with altered glycosylation patterns or amino acid substitutions, the system maintains the natural Fc receptor binding capability while adding new functionality - binding to the chimeric antigen receptor on T cells. This approach leverages the existing, well-characterized Fc domain structure and biology, avoiding the need for entirely new tag structures or molecular switches. The modified Fc domain serves multiple functions: maintaining antibody stability, enabling T cell recruitment via CAR binding, and preserving natural Fc receptor interactions. This multi-functionality based on a universal platform reduces production complexity compared to introducing completely new tagging systems, while maintaining high targeting precision.
Data Source
AI summary
The present invention generally relates to antigen binding receptors capable of specific binding to an Fc domain comprising the amino acid mutation P329G according to EU numbering. The present invention also relates to T cells, transduced with a antigen binding receptor which is recruited by specifically binding to/interacting with the mutated Fc domain of therapeutic antibodies. Furthermore, the invention relates to a kit comprising the transduced T cells of the invention and/or nucleic acid molecules, vectors encoding the antigen binding receptors of the present invention and tumor targeting antibodies comprising a mutated Fc domain.