Search

Simple Summary: TCR-mimics (TCRm) are designed to target intracellular tumor antigens presented by major histocompatibility complex (MHC) molecules on the surface of cancer cells. A TCRm imitates the capacity of T cells receptors (TCR) interact with peptide-MHC complexes (pMHC) to reach a broad range of intracellular targets with the unique strengths of high affinity and specificity of antibodies. This capability allows them to tackle previously "undruggable" targets for therapeutics when TCRm is engineered into different mechanisms of action like TCE or ADC. 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. [ABSTRACT FROM AUTHOR]

As the fastest growing class of therapeutic proteins, monoclonal antibodies (mAbs) represent a major potential drug class. Human antibodies are glycosylated in their native state and all clinically approved mAbs are produced by mammalian cell lines, which secrete mAbs with glycosylation structures that are similar, but not identical, to their human counterparts. Glycosylation of mAbs influences their interaction with immune effector cells that kill antibody-targeted cells. Here we demonstrate that human antibodies with specific human N-glycan structures can be produced in glycoengineered lines of the yeast Pichia pastoris and that antibody-mediated effector functions can be optimized by generating specific glycoforms. Glycoengineered P. pastoris provides a general platform for producing recombinant antibodies with human N-glycosylation. [ABSTRACT FROM AUTHOR]

Abstract: The growing antibody market and the pressure to improve productivity as well as reduce cost of production have fueled the development of alternative expression systems. The therapeutic function of many antibodies is influenced by N-linked glycosylation, which is affected by a combination of the expression host and culture conditions. This paper reports the generation of a glycoengineered Pichia pastoris strain capable of producing more than 1gl−1 of a functional monoclonal antibody in a robust, scalable and portable cultivation process with uniform N-linked glycans of the type Man5GlcNAc2. N-linked glycan uniformity and volumetric productivity have been maintained across a range of cultivation process conditions including pH (5.5–7.5), temperature (16–24°C), dissolved oxygen concentration (0.85–3.40mgl−1) and specific methanol feed rate (9–19mgg−1 h−1) as well as across different cultivation scales (0.5, 3.0, 15 and 40l). Compared to a marketed CHO-produced therapeutic antibody, the glycoengineered yeast-produced antibody has similar motilities on SDS-PAGE, comparable size exclusion chromatograms (SEC) and antigen binding affinities. This paper provides proof of concept that glycoengineered yeast can be used to produce functional full-length monoclonal antibodies at commercially viable productivities. [Copyright &y& Elsevier]