A Novel T-Cell Engaging Bi-specific Antibody Targeting the Leukemia Antigen PR1/HLA-A2

Herrmann, Amanda; Im, Jin S.; Pareek, Sumedha; Ruiz-Vasquez, Wilfredo; Lu, Shan; Сергеева, Анна; Mehrens, Jennifer; He, Hongchao; Alatrash, Gheath; Sukhumalchandra, Pariya; John, Lisa S. St.; Clise-Dwyer, Karen; Zha, Dongxing; Molldrem, Jeffrey J.

doi:10.3389/fimmu.2018.03153

Cited by 13 publications

(9 citation statements)

References 31 publications

(42 reference statements)

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“…The Molldrem group also developed a bsAB binding the PR1/HLA-A*02 complex and CD3 to improve the potency of the 8F4 mAB. This bsAB could activate T cells to lyse HLA-A*02 + primary AML blasts and cell lines [141]. Additionally, a TCR-like CAR with specificity for the PR1/HLA-A*02 complex, on the basis of the 8F4 mAB, was constructed, and transduced CAR T cells were capable to kill leukemia cell lines and primary AML blasts in vitro in an HLA-A*02-dependent manner [142].…”

Section: Hla-dependent Antigensmentioning

confidence: 99%

Antigen Targets for the Development of Immunotherapies in Leukemia

Bauer

Nelde

Bilich

et al. 2019

IJMS

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Immunotherapeutic approaches, including allogeneic stem cell transplantation and donor lymphocyte infusion, have significantly improved the prognosis of leukemia patients. Further efforts are now focusing on the development of immunotherapies that are able to target leukemic cells more specifically, comprising monoclonal antibodies, chimeric antigen receptor (CAR) T cells, and dendritic cell- or peptide-based vaccination strategies. One main prerequisite for such antigen-specific approaches is the selection of suitable target structures on leukemic cells. In general, the targets for anti-cancer immunotherapies can be divided into two groups: (1) T-cell epitopes relying on the presentation of peptides via human leukocyte antigen (HLA) molecules and (2) surface structures, which are HLA-independently expressed on cancer cells. This review discusses the most promising tumor antigens as well as the underlying discovery and selection strategies for the development of anti-leukemia immunotherapies.

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Section: Hla-dependent Antigensmentioning

confidence: 99%

Antigen Targets for the Development of Immunotherapies in Leukemia

Bauer

Nelde

Bilich

et al. 2019

IJMS

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“…This TCRm eliminated human AML in xenografts ( 224 ) and has now advanced to clinical trials. While active alone, to improve its potency 8F4 was engineered into a bi-specific T cell-engager (BiTE) to redirect polyclonal T cells to PR1-positive leukemias ( 225 ). The first fully human TCRm, ESK1, specific for a WT1-derived epitope/HLA-A*02:01 complex, was developed by our group ( 226 ).…”

Section: Tcr-based Non-cellular Therapiesmentioning

confidence: 99%

Empirical and Rational Design of T Cell Receptor-Based Immunotherapies

et al. 2021

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The use of T cells reactive with intracellular tumor-associated or tumor-specific antigens has been a promising strategy for cancer immunotherapies in the past three decades, but the approach has been constrained by a limited understanding of the T cell receptor’s (TCR) complex functions and specificities. Newer TCR and T cell-based approaches are in development, including engineered adoptive T cells with enhanced TCR affinities, TCR mimic antibodies, and T cell-redirecting bispecific agents. These new therapeutic modalities are exciting opportunities by which TCR recognition can be further exploited for therapeutic benefit. In this review we summarize the development of TCR-based therapeutic strategies and focus on balancing efficacy and potency versus specificity, and hence, possible toxicity, of these powerful therapeutic modalities.

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“…Herrmann et al also developed a TCR mimic-BiTE antibody with activity against certain tumors. (19) They used a TCR antibody (8F4) against the complex of HLA-A2 with a nonapeptide derived from proteinase-3 (P3) and neutrophil elastase (NE) (Table 1), which are highly expressed in AML blasts, multiple myeloma cells, and solid cancer. (20)(21)(22)(23)(24) It was demonstrated that 8F4 antibody can trigger CDC against AML cells in a HLA-A2-dependent manner when using AML cell lines and primary samples.…”

Section: Successful Preclinical Developmentsmentioning

confidence: 99%

Bringing Together the Power of T Cell Receptor Mimic and Bispecific Antibodies for Cancer Immunotherapy: Still a Long Way to Go

Shivarov

Blazhev

2021

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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Antibody-based cancer immunotherapy has revolutionized oncology. The first successful therapeutic antibodies relied on eliciting immune-mediated cytotoxicity (rituximab) or modulation of intracellular signaling (trastuzumab). Further attempts to enhance the antitumor effects led to the development of immunoconjugates with radioactive or cytotoxic compounds (tositumomab, brentuximab vedotin). Another line of research led to the bispecific antibodies that can enhance the formation of immunological synapse between cancer and cytotoxic T cells (blinatumomab). Despite the constant advances in design and production, the application of monoclonal antibodies in cancer treatment remains limited by the presence of specific cell surface markers. A rational approach to target intracellular cancer antigens was proposed almost two decades ago by the development of anti-peptide human leukocyte antigen (HLA) complex (T cell receptor-like/mimic) antibodies. They could recognize specifically cancer neoantigens expressed in the context of specific HLA molecules theoretically providing unprecedented specificity. Furthermore, they can be developed in a semigeneric format, that is, to target common neoantigens expressed in the context of common HLA molecules. It is rationale to expect that the development of such antibodies in the format of bispecific antibody constructs can bring together the power of specific antibody-based recognition and that of T cell-mediated lysis. There are already some preliminary reports that suggest such constructs would be an achievable goal. In this brief review, we discuss some of the successful preclinical developments in the field and the major challenges that are yet to be addressed.

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A Novel T-Cell Engaging Bi-specific Antibody Targeting the Leukemia Antigen PR1/HLA-A2

Cited by 13 publications

References 31 publications

Antigen Targets for the Development of Immunotherapies in Leukemia

Antigen Targets for the Development of Immunotherapies in Leukemia

Empirical and Rational Design of T Cell Receptor-Based Immunotherapies

Bringing Together the Power of T Cell Receptor Mimic and Bispecific Antibodies for Cancer Immunotherapy: Still a Long Way to Go

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