T-cell receptor therapy

One approach to overcome this hurdle is dual targeting by an antibody-T cell receptor (AbTCR) and a chimeric costimulatory signaling receptor (CSR) to two different antigens, in which both antigens are found together on the cancer cells, but not together on normal cells...By use of a AbTCR receptor comprising a newly developed TCR mimic monoclonal antibody (mAb) against the WT1 RMFPNAPYL (RMF) epitope/HLA-A2 complex, ESK2, and a secondary CSR comprising a scFv directed to CD33 linked to a truncated CD28 costimulatory fragment, this unique platform confers specific T cell cytotoxicity to the AML cells, while sparing healthy hematopoietic cells, including CD33+ myelomonocytic normal cells. These data suggest that this new platform, named AbTCR-CSR, through the combination of a AbTCR CAR and CSR could be an effective strategy to reduce toxicity and improve specificity and clinical outcomes in adoptive T cell therapy in AML.

Single-cell RNAseq analysis indicated activation of CD8+ T cells in regressing Raji tumors as well as clonal expansion of specific T cell receptors (TCRs). Cloning of TCRs from Raji-infiltrating T cells into a Jurkat reporter cell line showed reactivity specific for Raji tumor cells. Overall, we report a platform for studying in vivo human T cell tumor immunity by highlighting spontaneous Raji tumor regression, clonal TCR expansion, and T cell memory in HIS mice.

Surface-accessible pHLA complexes may be targeted with engineered T cell receptors or TCR mimetic antibodies reformatted to chimeric antigen receptors (CARs)...However, stimulating 41BB signaling pathways in the MAGE-A4 TCR T cells augmented long-term cytotoxicity. These data demonstrate that tumor-specific pHLA complexes can be potently targeted by both TCR and CAR-T cells, and that co-stimulatory signaling is necessary to mediate durable anti-tumor activity.

Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues...In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. This indicates that the same therapeutic levels are achieved with both regimens, which is beneficial for the treatment of disease.Conclusion This optimized odronextamab dosing regimen was associated with lower risk of CRS and lower levels of baseline cytokine levels compared with the original regimen. The drug exposure was lower in the first cycle when the risk of CRS is greater, but it was comparable to that of the original regimen after the full dose of treatment was received, ensuring that odronextamab dose levels required for efficacy are maintained.

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, eliciting T-cell-mediated cytotoxicity independent of T-cell receptor-mediated recognition. Simulated IL-6 profiles, obtained using the SC QSP model, showed the peak IL-6 values during Cycle 1 with the proposed SC step-up dosing regimen (2/26/100 mg) would not exceed those of 0.7/4/20 mg IV.Conclusion SC administration of odronextamab may be simpler and more convenient than IV dosing. PK and IL-6 modeling and simulation analyses enabled the identification of SC regimens for clinical evaluation, which may improve the tolerability while preserving the efficacy for the treatment of patients with B-cell NHL.

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. The model was also able to predict the CD8+ T-cell and B-cell profiles over time following IV odronextamab split-dosing regimen.Conclusion This QSP model was developed to address the safety concern related to CRS following treatment with odronextamab. The work demonstrated that the QSP modeling is a powerful tool that enabled optimization of odronextamab step-up dosing to minimize the risk of higher grade (i.e. Grade 2 and 3) CRS in lymphoma patients treated with odronextamab.

Odronextamab, a CD20xCD3 bispecific antibody that provides "signal 1" through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28CD8 T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL.

Despite the enormous promise of T cell therapies, the isolation and study of human T cell receptors (TCRs) of dedicated specificity remains a major challenge...[Figure: see text].

Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T-cell-mediated cytotoxicity independent of T-cell-receptor recognition. With step-up dosing, the highest-tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step-up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B-NHL.

Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. Time-to-event endpoints will be summarized by median and corresponding 95% CI using the Kaplan–Meier method. The study is actively accruing patients at sites across North America, Europe, and Asia-Pacific.

Background: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human CD20 x CD3 IgG4-based bispecific antibody that binds to CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity independent of T-cell receptor recognition. Preliminary analyses suggest that high levels of baseline tumor-infiltrating T cells may be associated with clinical response to odronextamab. Systemic T-cell homeostasis at baseline may be a potential predictor of clinical benefit with odronextamab, and further investigation is warranted. Although baseline CD20 expression level did not correlate with efficacy, loss of CD20 expression was observed frequently in progressive disease.

REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. This study is currently open to enrollment. Research Funding: Regeneron Pharmaceuticals Inc.