Molecular Determinants Regulating the Plasticity of the MHC Class II Immunopeptidome

Santambrogio, Laura

doi:10.3389/fimmu.2022.878271

Cited by 22 publications

(8 citation statements)

References 98 publications

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“…Although it has been done previously ( 47 – 50 ), de-immunizing key amino acid residues requires extensive modeling to determine the nonamer cores ( 51 ) within the identified suspect sequences. Unlike the closed binding pocket of MHC class I, the MHC class II binding pocket is open and more flexible ( 52 ). Within the nonamer cores, determining anchor residues in the binding pocket or those protruding into the TCR for possible replacement, would be key to de-immunization.…”

Section: Discussionmentioning

confidence: 99%

Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy

Penny,

Hainline,

Theoharis

et al. 2023

Front. Immunol.

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IntroductionIn oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics. MethodsHere we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration. ResultsTreatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm. DiscussionThese mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.

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Section: Discussionmentioning

confidence: 99%

Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy

Penny,

Hainline,

Theoharis

et al. 2023

Front. Immunol.

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“…The proprietary Cross-TAg Vector System ( Figure 7 ) adds sorting signals to a target protein as it is translated from the ivtRNA template in the cytosol of the DC. These sorting signals enable the protein to translocate to the endosomal-lysosomal pathway where peptides can be processed and selected by binding to class II HLA allotypes for transport to the cell surface, where they can activate CD4 T cells with complementary TCR ( 85 – 89 ).…”

Section: Module 2: Tcr Generationmentioning

confidence: 99%

Evolution by innovation as a driving force to improve TCR-T therapies

Schendel

2023

Front. Oncol.

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Adoptive cell therapies continually evolve through science-based innovation. Specialized innovations for TCR-T therapies are described here that are embedded in an End-to-End Platform for TCR-T Therapy Development which aims to provide solutions for key unmet patient needs by addressing challenges of TCR-T therapy, including selection of target antigens and suitable T cell receptors, generation of TCR-T therapies that provide long term, durable efficacy and safety and development of efficient and scalable production of patient-specific (personalized) TCR-T therapy for solid tumors. Multiple, combinable, innovative technologies are used in a systematic and sequential manner in the development of TCR-T therapies. One group of technologies encompasses product enhancements that enable TCR-T therapies to be safer, more specific and more effective. The second group of technologies addresses development optimization that supports discovery and development processes for TCR-T therapies to be performed more quickly, with higher quality and greater efficiency. Each module incorporates innovations layered onto basic technologies common to the field of immunology. An active approach of “evolution by innovation” supports the overall goal to develop best-in-class TCR-T therapies for treatment of patients with solid cancer.

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“…In pathological conditions, changes in the dendritic cell MHC-antigen processing and presentation machinery can affect the selection, affinity, composition, and epitope copy number of the MHC-ligandome ( 27 – 30 ). This is associated with up-regulation in the costimulatory molecule and increased adjuvanticity of the tissue microenvironment, which can tilt the T reg /T conv balance and favor autoreactivity ( 30 , 31 ).…”

Section: Recognition Of the Mhc-self-peptidome: Conventional And Regu...mentioning

confidence: 99%

The yin/yang balance of the MHC-self-immunopeptidome

Santambrogio

Franco

2022

Front. Immunol.

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The MHC-self immunopeptidome of professional antigen presenting cells is a cognate ligand for the TCRs expressed on both conventional and thymic-derived natural regulatory T cells. In regulatory T cells, the TCR signaling associated with MHC-peptide recognition induces antigen specific as well as bystander immunosuppression. On the other hand, TCR activation of conventional T cells is associated with protective immunity. As such the peripheral T cell repertoire is populated by a number of T cells with different phenotypes and different TCRs, which can recognize the same MHC-self-peptide complex, resulting in opposite immunological outcomes. This article summarizes what is known about regulatory and conventional T cell recognition of the MHC-self-immunopeptidome at steady state and in inflammatory conditions associated with increased T and B cell self-reactivity, discussing how changes in the MHC-ligandome including epitope copy number and post-translational modifications can tilt the balance toward the expansion of pro-inflammatory or regulatory T cells.

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Molecular Determinants Regulating the Plasticity of the MHC Class II Immunopeptidome

Cited by 22 publications

References 98 publications

Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy

Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy

Evolution by innovation as a driving force to improve TCR-T therapies

The yin/yang balance of the MHC-self-immunopeptidome

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