TCR–like antibodies mediate complement and antibody-dependent cellular cytotoxicity against Epstein-Barr virus–transformed B lymphoblastoid cells expressing different HLA-A*02 microvariants

Lai, Junyun; Choo, Joanna Ai Ling; Tan, Wei Jian; Too, Chien Tei; Oo, Min Zin; Suter, Manuel A.; Mustafa, Fatima; Srinivasan, Nalini; Chan, Conrad En Zuo; Lim, Andrew; Zhong, Youjia; Chan, Soh Ha; Hanson, Brendon J.; Gascoigne, Nicholas R. J.; MacAry, Paul A.

doi:10.1038/s41598-017-10265-6

Cited by 13 publications

(10 citation statements)

References 34 publications

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“…Our proof-of-concept experiments demonstrated that PGA/Alum efficiently enhances the humoral and cellular immune responses specific to both OVA (a model antigen) and the influenza vaccine antigen (a vaccine antigen of a representative infectious disease). Importantly, we found that PGA/Alum significantly increased ADCC, which has recently been shown to induce effective protection against various viruses, including Ebola (9), human immunodeficiency virus (43, 44), Epstein-Barr virus (45), and influenza viruses (8, 32). Our results from an ADCC assay performed using mouse serum revealed that PGA/Alum enhanced ADCC activity.…”

Section: Discussionmentioning

confidence: 79%

Poly-γ-Glutamic Acid Complexed With Alum Induces Cross-Protective Immunity of Pandemic H1N1 Vaccine

Nguyen¹,

Kwak²,

Lee³

et al. 2019

Front. Immunol.

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The use of a good vaccine adjuvant may induce a higher immunogenicity profile of vaccine antigens. Here, we developed a new adjuvant by combining poly-γ-glutamic acid (γ-PGA) with alum (PGA/Alum) and investigated its ability to enhance the immunogenicity and the cross-reactive efficacy of pandemic H1N1 (pH1N1) influenza vaccine antigen. PGA/Alum enhanced antigen delivery to draining lymph nodes and antigen-specific immunogenicity in mice using OVA as a model antigen. It also greatly increased OVA-specific antibody production, cytotoxic T lymphocyte (CTL) activity, and antibody-dependent cellular cytotoxicity (ADCC). These abilities of PGA/Alum improved the protective efficacy of pH1N1 vaccine antigen by increasing hemagglutination-inhibition titers, enhancing ADCC and CTL activity, and speeding viral clearance following homologous viral challenge. Importantly, the cross-protective efficacy of pH1N1 vaccine against heterologous viruses [A/Puerto Rico/8/34 (H1N1) and A/Hong Kong/1/1968 (H3N2)] was significantly enhanced by PGA/Alum, and cross-reactive ADCC and CTL activities were observed. Together, our results strongly suggest that PGA/Alum may be a promising vaccine adjuvant for preventing influenza and other infectious diseases.

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Section: Discussionmentioning

confidence: 79%

Poly-γ-Glutamic Acid Complexed With Alum Induces Cross-Protective Immunity of Pandemic H1N1 Vaccine

Nguyen¹,

Kwak²,

Lee³

et al. 2019

Front. Immunol.

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“…The high-affinity TCR-like Ab C1-17 can be converted into a bispecific T-cell engager [ 20 ] and a chimeric antigen receptor (CAR) for CAR-T therapy based on the autologous T-cells to overcome allogeneic immunogenicity [ 3 , 26 ]. Moreover, C1-17 can be developed as a therapeutic Ab to eliminate CMV-infected cells through the effecter functions, such as Ab-dependent cellular cytotoxicity [ 27 , 28 ], or via a targeting agent to deliver cytotoxic payloads, such as potent drugs and toxins [ 9 , 29 ]. Comparative analyses of CTL responses in CMV-seropositive individuals have shown that, among the CMV-derived CTL epitopes, the pp65-derived CMVpp65 495-503 and the major immediate-early gene product (IE-1)-derived VLEETSVML peptide (residues 316–324) are the most frequent CTL epitope peptides, with the former being more dominant than the latter [ 5 , 6 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Affinity Maturation of a T-Cell Receptor-Like Antibody Specific for a Cytomegalovirus pp65-Derived Peptide Presented by HLA-A*02:01

Lee

Son

et al. 2021

IJMS

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Human cytomegalovirus (CMV) infection is widespread among adults (60–90%) and is usually undetected in healthy individuals without symptoms but can cause severe diseases in immunocompromised hosts. T-cell receptor (TCR)-like antibodies (Abs), which recognize complex antigens (peptide–MHC complex, pMHC) composed of MHC molecules with embedded short peptides derived from intracellular proteins, including pathogenic viral proteins, can serve as diagnostic and/or therapeutic agents. In this study, we aimed to engineer a TCR-like Ab specific for pMHC comprising a CMV pp65 protein-derived peptide (495NLVPMVATV503; hereafter, CMVpp65495-503) in complex with MHC-I molecule human leukocyte antigen (HLA)-A*02:01 (CMVpp65495-503/HLA-A*02:01) to increase affinity by sequential mutagenesis of complementarity-determining regions using yeast surface display technology. Compared with the parental Ab, the final generated Ab (C1-17) showed ~67-fold enhanced binding affinity (KD ≈ 5.2 nM) for the soluble pMHC, thereby detecting the cell surface-displayed CMVpp65495-503/HLA-A*02:01 complex with high sensitivity and exquisite specificity. Thus, the new high-affinity TCR-like Ab may be used for the detection and treatment of CMV infection.

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“…Previous attempts to generate TCR-like mAbs against EBV antigen based on mouse immunization strategies (15,16) resulted murine mAbs against peptides derived from LMP1, LMP2 (CLG), and EBNA-1, in the context of HLA-A*02:01 and related suballeles (12). Of these antibodies, only the EBNA-1 TCR-like mAb was shown to modestly improve survival in immunodeficient mice implanted with EBV + BLCLs.…”

Section: Discussionmentioning

confidence: 99%

TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignancies

et al. 2018

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EBV infection is associated with a number of malignancies of clinical unmet need, including Hodgkin lymphoma, nasopharyngeal carcinoma, gastric cancer, and posttransplant lymphoproliferative disease (PTLD), all of which express the EBV protein latent membrane protein 2A (LMP2A), an antigen that is difficult to target by conventional antibody approaches. To overcome this, we utilized phage display technology and a structure-guided selection strategy to generate human T cell receptor-like (TCR-like) monoclonal antibodies with exquisite specificity for the LMP2A-derived nonamer peptide, C426LGGLLTMV434 (CLG), as presented on HLA-A*02:01. Our lead construct, clone 38, closely mimics the native binding mode of a TCR, recognizing residues at position P3-P8 of the CLG peptide. To enhance antitumor potency, we constructed dimeric T cell engaging bispecific antibodies (DiBsAb) of clone 38 and an affinity-matured version clone 38-2. Both DiBsAb showed potent antitumor properties in vitro and in immunodeficient mice implanted with EBV transformed B lymphoblastoid cell lines and human T cell effectors. Clone 38 DiBsAb showed a stronger safety profile compared with its affinity-matured variant, with no activity against EBV- tumor cell lines and a panel of normal tissues, and was less cross-reactive against HLA-A*02:01 cells pulsed with a panel of CLG-like peptides predicted from a proteomic analysis. Clone 38 was also shown to recognize the CLG peptide on other HLA-A*02 suballeles, including HLA-A*02:02, HLA-A*02:04, and HLA-A*02:06, allowing for its potential use in additional populations. Clone 38 DiBsAb is a lead candidate to treat EBV malignancies with one of the strongest safety profiles documented for TCR-like mAbs.

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TCR–like antibodies mediate complement and antibody-dependent cellular cytotoxicity against Epstein-Barr virus–transformed B lymphoblastoid cells expressing different HLA-A*02 microvariants

Cited by 13 publications

References 34 publications

Poly-γ-Glutamic Acid Complexed With Alum Induces Cross-Protective Immunity of Pandemic H1N1 Vaccine

Poly-γ-Glutamic Acid Complexed With Alum Induces Cross-Protective Immunity of Pandemic H1N1 Vaccine

Affinity Maturation of a T-Cell Receptor-Like Antibody Specific for a Cytomegalovirus pp65-Derived Peptide Presented by HLA-A*02:01

TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignancies

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