Most traditional antibodies target cell surface antigens (such as PD-1 and PD-L1) or soluble antigens. However, ideal tumor antigens are often intracellular (such as RAS, P53, and WT1). Endogenous T cell receptors (TCRs) can recognize intracellular antigens/HLA complexes through MHC-antigen-peptide (MAP) complexes, thereby activating T cells against tumor cells. However, their affinity for antigens is low, which often leads to tumor immune escape. Protheragen developed the innovative TCR-mimic (TCRm) antibody platform to discover TCRm antibodies with higher affinity and specificity than endogenous TCRs.

Introduction to TCR-mimic Antibodies

T cell receptor-mimic (TCRm) antibodies are a groundbreaking class of biologics engineered to recognize intracellular antigens by targeting peptide-MHC complexes on the cell surface. Unlike conventional antibodies that bind to surface proteins, TCRm antibodies emulate the specificity of natural T cell receptors, enabling them to detect disease-associated peptides derived from intracellular proteins, such as viral antigens or cancer neoantigens, that are otherwise inaccessible to traditional therapeutics. This unique mechanism unlocks opportunities to target previously "undruggable" intracellular targets, opening new avenues for precision therapies in oncology, infectious diseases, and beyond.

Fig.1 Mechanism of a TCR-mimic (TCRm) antibody targeting an intracellular peptide presented by MHC. (Li D, et al., 2017)

Challenges in TCR-mimic Antibody Development

The development of TCR-mimic (TCRm) antibodies faces several formidable challenges, primarily due to the low immunogenicity and structural complexity of peptide-MHC (pMHC) targets. Generating antibodies with sufficient affinity and specificity is difficult, as the target epitope is a composite of the peptide and MHC molecule, requiring precise molecular recognition. Additionally, achieving cross-reactivity with specific HLA alleles while avoiding off-target binding to similar pMHC complexes poses significant hurdles in ensuring therapeutic safety. These obstacles necessitate advanced immunization strategies and sophisticated screening platforms to identify functional TCRm antibodies with drug-like properties.

GeniusTCR™: Fully Human TCR-mimic Antibody Platform

Protheragen's proprietary GeniusTCR™ platform integrates a novel transgenic mouse model with our high-throughput antibody screening technology to enable one-step in vivo generation of fully human, high-affinity antibodies targeting human peptide-MHC complexes (pMHC). This innovative approach bypasses the traditional limitations of TCRm antibody development by directly engaging the native immune system to produce optimized candidates against intracellular targets. The platform ensures superior specificity and developability, accelerating the discovery of therapeutics for previously undruggable disease drivers.

Fig.2 Fully human TCR-mimic (TCRm) antibody discovery process.

Advantages of GeniusTCR™ Platform

The GeniusTCR™ platform represents a paradigm shift in TCR-mimic antibody development by integrating cutting-edge transgenic technology with advanced screening methodologies. This powerful combination directly addresses the historical challenges of targeting intracellular antigens, delivering unprecedented efficiency and success rates in generating therapeutic candidates.

Integrated Discovery Efficiency

The GeniusTCR™ platform synergizes our proprietary transgenic mouse with high-throughput screening systems, enabling one-step in vivo generation of fully human antibodies that recognize human peptide-MHC complexes with high affinity.

Superior Targeting Properties

Antibodies selected through our screening process demonstrate significantly enhanced affinity and specificity compared to natural T-cell receptors (TCRs), enabling more precise targeting of intracellular antigens.

Optimized Antibody Diversity

Comprehensive in-situ replacement and modification of large genomic segments in GeniusTCR™ mice ensure the generation of a highly diverse antibody repertoire, providing an optimal foundation for discovering functional TCR-mimic antibodies.

Accelerated Screening Workflow

Our antibody discovery pipeline incorporates the Beacon Optofluidic system for high-throughput screening and subsequent sequencing analysis, dramatically reducing development timelines while significantly improving screening efficiency and success rates.

Applications of the GeniusTCR™ Platform

The GeniusTCR™ platform enables groundbreaking therapeutic and diagnostic applications by unlocking access to previously undruggable intracellular targets. Our technology demonstrates exceptional versatility across multiple disease areas and development scenarios.

Case Study

KRAS G12V_7-16/HLA-A03 TCRm Antibody

• Specifically binds to the G12V mutation and the HLA-A03 allele
• High affinity and no binding to potential off-target peptides
• Bispecific T cell engager, KRAS G12V_7-16/HLA-A03 x CD3
• Specific in vivo cytotoxic activity

Fig.3 The bispecific antibody KRAS G12V_7-16/HLA-A03 × CD3nano T cell engager exhibits specific cytotoxic activity.

Pipeline

Leveraging cutting-edge technology and a talented team, Protheragen has developed the GeniusTCR™ fully human TCR-mimic (TCRm) antibody platform. By immunizing GeniusTCR™ mice, we can directly generate a diverse set of peptide/HLA-targeted antibodies for subsequent screening and development. These antibodies exhibit high specificity and minimal off-target toxicity, reducing the potential for tumor immune escape. Furthermore, our innovative mouse models and in vitro/in vivo pharmacology platforms effectively streamline the preclinical candidate (PCC) screening process. Contact us today to explore collaboration opportunities and accelerate your drug development pipeline.