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TCRm Antibody

TCR Mimic Antibodies

Why TCRm antibody
Advantages of TCRm Antibodies
TCRm Derived T Cell Engagers
Promising Preclinical Results

Why TCRm Antibody?

TCR mimic (TCRm) antibodies are an emerging class of therapeutic antibodies that target intracellular tumor antigens presented by MHC molecules, offering several advantages over traditional antibody therapies. These include targeting a broader range of antigens, off-the-shelf drug development, and combining T-cell receptor specificity with antibody pharmacological properties. Compared to traditional TCR therapies, TCRm antibodies achieve higher affinities and broader applicability, potentially overcoming limitations such as HLA restriction. Nona Biosciences’ TCRm antibodies, in particular, stand out for their high affinity, specificity, and innovative design, positioning them as a promising option in cancer immunotherapy.

Advantages of TCRm Antibodies

TCRm antibodies offer several key advantages over traditional antibody and TCR-based therapies:

  • Ability to target intracellular antigens:

TCRm antibodies can recognize peptides derived from intracellular proteins presented on MHC molecules, expanding the range of targetable antigens compared to surface-bound targets of traditional antibodies. This capability allows for identifying and targeting a broader array of disease-associated proteins, potentially leading to more effective treatments.

  • Higher affinity than natural TCRs:

Through in vitro selection, TCRm antibodies can achieve affinities orders of magnitude higher than TCRs, reaching the subnanomolar range. This increased affinity can potentially enhance their therapeutic efficacy.

  •  Antibody-like pharmacological properties:

TCRm antibodies exhibit several favorable drug-like properties. They possess a long half-life, which allows for sustained therapeutic action. Additionally, they are stable, ensuring consistent performance over time.

  • Engaging multiple MOA:

TCRm antibodies can mediate tumor cell killing through various antibody-dependent mechanisms like ADCC and CDC. Additionally, they exhibit TCR-like recognition of specific peptide-MHC complexes, providing a multifaceted approach to targeting and eliminating cancer cells.

  • Ease of manufacturing

Compared to TCR-based therapies, TCRm antibodies are easier to produce, making them more accessible for large-scale clinical applications.

Advantages of TCRm Antibodies

TCRm antibodies offer several key advantages over traditional antibody and TCR-based therapies:

  • Ability to target intracellular antigens:

TCRm antibodies can recognize peptides derived from intracellular proteins presented on MHC molecules, expanding the range of targetable antigens compared to surface-bound targets of traditional antibodies. This capability allows for identifying and targeting a broader array of disease-associated proteins, potentially leading to more effective treatments.

  • Higher affinity than natural TCRs:

Through in vitro selection, TCRm antibodies can achieve affinities orders of magnitude higher than TCRs, reaching the subnanomolar range. This increased affinity can potentially enhance their therapeutic efficacy.

  •  Antibody-like pharmacological properties:

TCRm antibodies exhibit several favorable drug-like properties. They possess a long half-life, which allows for sustained therapeutic action. Additionally, they are stable, ensuring consistent performance over time.

  • Engaging multiple MOA:

TCRm antibodies can mediate tumor cell killing through various antibody-dependent mechanisms like ADCC and CDC. Additionally, they exhibit TCR-like recognition of specific peptide-MHC complexes, providing a multifaceted approach to targeting and eliminating cancer cells.

  • Ease of manufacturing

Compared to TCR-based therapies, TCRm antibodies are easier to produce, making them more accessible for large-scale clinical applications.

TCRm Derived T Cell Engagers

TCRm antibodies can be engineered into bispecific T cell engager (TCE) formats to enhance their therapeutic potential. TCRm-derived TCEs, composed of two linked scFvs, target a TAA and CD3 on T cells, redirecting T cells to kill tumor cells. Incorporating a TCRm antibody as the tumor-targeting component allows TCRm-based TCEs to recognize intracellular antigens presented on MHC molecules, expanding the range of targetable antigens. TCRm-based TCEs engage polyclonal T cells without ex vivo manipulation, offer enhanced tumor specificity due to high affinity and specificity, and induce potent T cell-mediated cytotoxicity against tumor cells expressing low levels of target antigen, highlighting their promise in cancer immunotherapy.

TCRm Derived T Cell Engagers

TCRm antibodies can be engineered into bispecific T cell engager (TCE) formats to enhance their therapeutic potential. TCRm-derived TCEs, composed of two linked scFvs, target a TAA and CD3 on T cells, redirecting T cells to kill tumor cells. Incorporating a TCRm antibody as the tumor-targeting component allows TCRm-based TCEs to recognize intracellular antigens presented on MHC molecules, expanding the range of targetable antigens. TCRm-based TCEs engage polyclonal T cells without ex vivo manipulation, offer enhanced tumor specificity due to high affinity and specificity, and induce potent T cell-mediated cytotoxicity against tumor cells expressing low levels of target antigen, highlighting their promise in cancer immunotherapy.

Nona Biosciences Promising Preclinical Results

Nona Biosciences has generated compelling data demonstrating the capabilities and potential of the TCRm antibody platform. The TCRm antibodies exhibit high affinity and specificity for target antigens, enabled by using high-quality internally generated pMHC and mRNA-encoded pMHC immunogens in their discovery process.

The internally generated mRNA-encoding pMHC immunogen effectively stimulate an immune response

Nona’s TCRm-CD3 engager design, which combines an anti-CD3 nanobody with a TCRm Fab and incorporates Fc-silencing modifications, has shown promising therapeutic potential. In preclinical studies, Nona’s TCRm-CD3 engagers demonstrated potent and concentration-dependent cytotoxicity against tumor cells expressing the target antigen, highlighting their efficacy.

TCRmxCD3 TCE-1
TCRmxCD3 TCE-2

Cytotoxicity of the TCRm-CD3 engagers against OVCAR3 and NCI-H1703 cells indicates that TCRm Abs induce the killing effect on tumor cells.

Furthermore, Nona’s TCRm antibodies have achieved subnanomolar affinities for their targets, which are orders of magnitude higher than the affinities of natural TCRs, which typically range from 1-100 μM. This high affinity can potentially enhance the therapeutic efficacy of Nona’s TCRm antibodies.

TCR, detected by Octet
TCR mimic Ab, detected by Octet

Specific and High Affinity Binding. The identification of TCRm antibodies with specific and high affinity to target-pMHC proteins.

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