Elimination of large tumors in mice by mRNA-encoded bispecific antibodies
Abstract
The potential of bispecific T cell-engaging antibodies is hindered by manufacturing challenges and short serum half-life. We circumvented these limitations by treating mice with in vitro-transcribed pharmacologically optimized, nucleoside-modified mRNA encoding the antibody. We achieved sustained endogenous synthesis of the antibody, which eliminated advanced tumors as effectively as the corresponding purified bispecific antibody. Because manufacturing of pharmaceutical mRNA is fast, this approach could accelerate the clinical development of novel bispecific antibodies.
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An alternative strategy to avoid poly(A) instability consists of including an internal 10-nucleotide linker into the poly(A) stretch.
“An alternative strategy has been developed to avoid this instability, consisting of including an internal 10-nucleotide linker into the poly(A) stretch.25,26”
From Combining an optimized mRNA template with a double purification process allows strong expression of in vitro transcribed mRNA (2021) · cites this paper as [25]
A short UGC linker can be included in the poly(A) tail to overcome the stability issue.
“A solution to overcome this stability issue is to include a short UGC linker in the poly(A) tail30,31.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [30]
Lipid nanoparticle-mRNA formulations have been investigated for ex vivo engineering of CAR T cells and for the production of antibodies, such as anti-CD20, anti-human epidermal growth factor receptor 2 and anti-CD3/claudin 6.
“Lipid nanoparticle–mRNA formulations have also been investigated for ex vivo engineering of CAR T cells217 and for the production of antibodies, such as anti-CD20 (ref.146), anti-human epidermal growth factor receptor 2 (HER2)95 and anti-CD3/claudin 6 (ref.147).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [147]
This mRNA platform represented a valid alternative to classic mRNA cancer vaccines, providing a strong infiltration of T cells able to eliminate tumors in mice.
“This mRNA platform represented a valid alternative to classic mRNA cancer vaccines, providing a strong infiltration of T cells able to eliminate tumors in mice.”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [197]
Stadler et al. designed mRNA constructs that encode bispecific antibodies directed against the T cell receptor associated molecule CD3 and tumor antigens, referred to as RiboMABs.
“Stadler et al. designed mRNA constructs that encode bispecific antibodies directed against the T cell receptor associated molecule CD3 and tumor antigens, referred to as RiboMABs [197].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [197]
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- Authors
- Stadler, C. R., Bähr-Mahmud, H., Celik, L., Hebich, B., Roth, A. S., Roth, R. P., Karikó, K., Türeci, Ö., & Sahin, U.
- Affiliations
- BioNTech (Germany) (DE)
- Venue
- Nature Medicine
- Published
- 2017-06-12
- Volume
- 23
- Issue
- 7
- Pages
- 815-817
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2626337750
- Cited by
- 290
- References
- 19
- Citations by year
- 2026: 33 · 2025: 44 · 2024: 32 · 2023: 47 · 2022: 29 · 2021: 31 · 2020: 24 · 2019: 18 · 2018: 24 · 2017: 8
- FWCI
- 15.52
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-10-01)
- Open access
- closed
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- bispecific antibodies, T cell-engaging antibody, mRNA vaccines, in vitro transcribed mRNA, nucleoside-modified mRNA, tumor rejection, T cell-mediated antitumor immunity
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Luminescent Measurements, Male, Mice, Inbred BALB C, Neoplasms, RNA, Messenger, T-Lymphocytes, Immunoblotting, Cytokines, Mice, Inbred NOD, Antibodies, Bispecific, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Mice, In Vitro Techniques
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