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Time-dependent enhancement of mRNA vaccines by 4-1BB costimulation.

ABSTRACT: mRNA vaccines have demonstrated efficacy against COVID-19. However, concerns regarding waning immunity and breakthrough infections have motivated the development of next-generation vaccines with enhanced efficacy. In this study, we investigated the impact of 4-1BB costimulation on immune responses elicited by mRNA vaccines in mice. We first vaccinated mice with an mRNA vaccine encoding the SARS-CoV-2 spike antigen like the Moderna and Pfizer-BioNTech vaccines, followed by administration of 4-1BB costimulatory antibodies at various times post-vaccination. Administering 4-1BB costimulatory antibodies during the priming phase did not enhance immune responses. However, administering 4-1BB costimulatory antibodies after 96 hours elicited a significant improvement in CD8 T cell responses, leading to enhanced protection against breakthrough infections. A similar improvement in immune responses was observed with multiple mRNA vaccines, including vaccines against common cold coronavirus, human immunodeficiency virus (HIV), and arenavirus. These findings demonstrate a time-dependent effect by 4-1BB costimulation and provide insights for developing improved mRNA vaccines.

SUBMITTER: Sanchez S

PROVIDER: S-EPMC10942304 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Time-dependent enhancement of mRNA vaccines by 4-1BB costimulation.

Sanchez Sarah S Dangi Tanushree T Awakoaiye Bakare B Irani Nahid N Fourati Slim S Richner Justin J Penaloza-MacMaster Pablo P

bioRxiv : the preprint server for biology 20240304

mRNA vaccines have demonstrated efficacy against COVID-19. However, concerns regarding waning immunity and breakthrough infections have motivated the development of next-generation vaccines with enhanced efficacy. In this study, we investigated the impact of 4-1BB costimulation on immune responses elicited by mRNA vaccines in mice. We first vaccinated mice with an mRNA vaccine encoding the SARS-CoV-2 spike antigen like the Moderna and Pfizer-BioNTech vaccines, followed by administration of 4-1BB ...[more]

PMID: 38496467

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Project description:BackgroundImmune checkpoint inhibitors have revolutionized cancer therapy, but many patients fail to respond or develop resistance, often due to reduced T cell activity. Costimulation via 4-1BB has emerged as a promising approach to enhance the effector function of antigen-primed T cells. Bispecific T cell-engaging (TCE) antibodies are an effective way to provide tumor-specific T cell receptor-mediated signaling to tumor-infiltrating lymphocytes. mRNA-based delivery of bispecific antibodies, offer a novel approach to enhance tumor-specific immune responses while minimizing adverse effects.MethodsTwo bispecific antibodies were generated: the EGFR x CD3 TCE antibody (LiTE) and the PD-L1 x 4-1BB costimulatory antibody (LiTCo), which was further fused to a high FcRn albumin variant (Albu-LiTCo). The mRNA encoding these bispecific antibodies contains an N1-methylpseudouridine modified nucleoside and regulatory sequences to ensure proper expression and stability. A series of in vitro assays and cell-based analyses were performed to characterize both antibodies. The in vivo efficacy of the mRNA-encoded bispecific antibodies was evaluated in xenograft tumor models expressing EGFR.ResultsWe investigated the combined effect of two mRNA-encoded Fc-free bispecific antibodies with complementary mechanisms of action: an EGFR-targeting TCE and a half-life extended PD-L1 x 4-1BB costimulatory antibody. The mRNAs encoding both bispecific LiTERNA and Albu-LiTCoRNA, showed similar binding specificity and in vitro function to their protein analogues. Pharmacokinetic studies demonstrated sustained expression of both bispecific antibodies following intravenous administration of the mRNAs formulated using a polymer/lipid-based nanoparticle (LNP) but different pharmacokinetic profiles, shorter for the TCE and longer for the PD-L1 x 4-1BB. When administered as a mRNA-LNP combination (ComboRNA), the growth of EGFR-positive tumors in immunocompetent mice was significantly inhibited, resulting in tumor regression in 20% of cases with no associated toxicity. Histological analysis confirmed increased T cell infiltration in the tumors treated with LITERNA and ComboRNA. Repeated administration resulted in sustained production of bispecific antibodies with different exposure cycles and potent antitumor activity with a favorable safety profile.ConclusionsThese results highlight the potential of combining two mRNA-encoded bispecific antibodies with different mechanisms of action and programmable half-life for cancer immunotherapy.

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Time-dependent enhancement of mRNA vaccines by 4-1BB costimulation.

Publications

Time-dependent enhancement of mRNA vaccines by 4-1BB costimulation.

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