Unlocking Intracellular Oncology Targets: The Unique Role of Antibody-Based T-Cell Receptor Mimic (TCRm) Therapeutics in T-Cell Engagers (TCEs) and Antibody-Drug Conjugates (ADCs).

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This review focuses on the innovative use of T-cell receptor mimic (TCRm) antibodies within the therapeutic frameworks of T-cell engagers (TCE) and antibody-drug conjugates (ADCs). TCRm antibodies, designed to recognize peptide-MHC complexes rather than cell surface proteins, integrate the capacity of T-cells to reach intracellular targets with the unique strengths of antibodies. When incorporated into T-cell engaging therapeutics, TCRms redirect T cells to cancer cells, facilitating direct cytotoxicity. In ADCs, TCRm antibodies deliver cytotoxic agents with highly specific targeting to cancer cells, sparing healthy tissues. Together, these antibody-based strategies represent a significant leap forward in oncology, opening new avenues for the treatment of cancers previously deemed untreatable, with other potential applications in autoimmune diseases. This review discusses the mechanisms, clinical advancements, and future prospects of these cutting-edge therapies, highlighting their potential to transform the landscape of cancer treatment.