pMHC-Targeted Radioconjugates for Low-Density Tumor Antigens
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Solution Overview
Problem
Existing cancer therapies, such as TCR-based and antibody-based treatments, struggle to effectively target intracellular tumor antigens due to low expression density and immunosuppressive environments within tumors, limiting their therapeutic efficacy.
Innovation Solution
Development of recombinant TCRs and TCR-mimic antibodies conjugated to radionuclides that specifically target Major Histocompatibility Complex (MHC)-presented peptides, enabling radiation-induced feed-forward mechanism for tumor ablation, even in low expression scenarios.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCR-based or antibody-based therapies are used to target tumor antigens, then specific recognition of tumor cells is achieved, but therapeutic efficacy is limited due to low target expression density and immunosuppressive tumor environments
Solution Approach 1:
The patent changes the mechanism of action from immune-mediated cytotoxicity to direct radiation-induced cell death. By conjugating radionuclides to TCRs or TCR-mimic antibodies, the therapy delivers ionizing radiation directly to tumor cells expressing low levels of pMHC antigens, overcoming the limitation of low target expression density that plagues conventional TCR and antibody therapies
Solution Approach 2:
The patent replaces the biological mechanism (immune cell-mediated killing) with a physical mechanism (radiation-induced DNA damage). The radionuclide-conjugated biologics deliver radiation energy directly to the tumor cell, substituting the complex immune recognition and killing pathway with a more direct and potent physical destruction mechanism that is less susceptible to immunosuppression
2Reliability
If immune checkpoint inhibitors or cell-based therapies are administered, then adaptive immune response is enhanced, but durable response is not achieved due to tumor immunosuppression and physical barriers
Solution Approach 1:
The patent replaces immune-mediated killing mechanisms with direct radiation-induced cell death. The radionuclide-conjugated TCR or TCR-mimic antibody delivers ionizing radiation that causes double-strand DNA breaks and apoptosis directly in the tumor cell, bypassing the immunosuppressive tumor microenvironment that prevents durable responses to checkpoint inhibitors and cell-based therapies
Solution Approach 2:
The radionuclide-conjugated biologic serves as an intermediary that bridges specific tumor recognition (via TCR or TCR-mimic antibody binding to pMHC) and direct cell killing (via radiation). This intermediary approach allows the therapy to overcome physical barriers and immunosuppression by delivering cytotoxic radiation directly to the tumor cell without requiring activation of immune effector functions
3Reliability
If recombinant TCR or TCR-mimic antibodies are used with Fc-immune effector functions, then tumor cell killing is attempted, but effectiveness is insufficient due to low pMHC density on tumor cell surface
Solution Approach 1:
The patent changes the killing mechanism from dependence on immune effector functions (which require high target density for effective ADCC or CDC) to direct radiation-induced cell death. The radionuclide emits ionizing radiation that causes lethal DNA damage even at low target engagement levels, making the therapy effective against tumors with low pMHC expression that would be insufficient for Fc-mediated killing
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 radiolabeled biologics can effectively target and ablate tumors with low target expression levels, overcoming immunosuppression and physical barriers, and induce increased pMHC expression, enhancing therapeutic outcomes.
Implementation Method 1
compositions including a soluble radiolabeled biologic that binds specifically to a complex composed of an antigen-presenting molecule such as a Major Histocompatibility Complex (MHC) having a peptide bound or restricted thereon
Data Source
AI summary
Radionuclide-labeled soluble biologics directed against peptide presenting Major Histocompatibility Complexes (pMHCs), and methods for treating cancers using the biologics are provided. Soluble biologics include recombinant T-cell receptor proteins (rTCR) and TCR-antibody mimics that specifically bind to pMHCs. The soluble biologics may further include a heavy chain of IgG1, IgG2, IgG4, or variants thereof. The radioisotopes used to label the soluble biologic may include alpha-emitting isotopes, such as actinium-225, or beta-emitting isotopes, such as lutetium-177, and may be administered at a maximum tolerated dose in a single bolus or in fractionated doses that together equal the maximum tolerated dose. The methods may further include administration of additional therapeutic agents or modalities.