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. 2023 Oct 16;12(1):2255041.
doi: 10.1080/2162402X.2023.2255041. eCollection 2023.

Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody

Hayat Bähr-Mahmud  1 , Ursula Ellinghaus  1 , Christiane R Stadler  1 , Leyla Fischer  1 , Claudia Lindemann  1 , Anuhar Chaturvedi  1 , Jan Diekmann  1 , Stefan Wöll  1 , Imke Biermann  1 , Bernhard Hebich  1 , Caroline Scharf  1 , Manuela Siefke  1 , Alexandra S Roth  1 , Martin Rao  1 , Kerstin Brettschneider  1 , Eva-Maria Ewen  1 , Uğur Şahin  1   2 , Özlem Türeci  1   3
Affiliations

Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody

Hayat Bähr-Mahmud et al. Oncoimmunology. .

Abstract

IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).

Keywords: ADCC; BNT141; IMAB362; RNA therapeutics; RiboMab; Zolbetuximab; human CLDN18.2; immunotherapy; solid tumor.

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Conflict of interest statement

All authors are current or former employees of, and own stock and/or stock options in, BioNTech SE. Ö.T. is the Chief Medical Officer of BioNTech SE and is named as an inventor on patents related to IMAB362/Zolbetuximab. U.Ş. is the Chief Executive Officer of BioNTech SE. A patent application has been submitted by BioNTech SE for BNT141. H.B-M., U.E., C.R.S., L.F., C.L., J.D., K.B., U.Ş., and Ö.T. are named as inventors on issued or pending patents related to BNT141. U.Ş. and Ö.T. have received royalties and consultancy fees from Astellas Pharma.

Figures

Figure 1.
Figure 1.
BNT141-encoded RiboMab01 produced in vitro is biologically active.
Figure 2.
Figure 2.
Weekly BNT141 administration slows tumor growth and results in stable exposure to biologically functional RiboMab01 in mice.
Figure 3.
Figure 3.
Repeated dosing of nonhuman primates with BNT141 results in sustained serum levels of functional RiboMab01.
See this image and copyright information in PMC

References

    1. Sahin U, Koslowski M, Dhaene K, Usener D, Brandenburg G, Seitz G, Huber C, Türeci Ö. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008 Dec 1;14(23):7624–9. doi:10.1158/1078-0432.CCR-08-1547. - DOI - PubMed
    1. Türeci Ö, Koslowski M, Helftenbein G, Castle J, Rohde C, Dhaene K, Seitz G, Sahin U.. Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals. Gene. 2011 Aug 1;481(2):83–92. doi:10.1016/j.gene.2011.04.007. - DOI - PubMed
    1. Coati I, Lotz G, Fanelli GN, Brignola S, Lanza C, Cappellesso R, Pellino A, Pucciarelli S, Spolverato G, Guzzardo V, et al. Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases. Br J Cancer. 2019. Jul;121(3):257–263. doi:10.1038/s41416-019-0508-4. - DOI - PMC - PubMed
    1. Karanjawala ZE, Illei PB, Ashfaq R, Infante JR, Murphy K, Pandey A, Schulick R, Winter J, Sharma R, Maitra A, et al. New markers of pancreatic cancer identified through differential gene expression analyses: claudin 18 and annexin A8. Am J Surg Pathol. 2008. Feb;32(2):188–196. doi:10.1097/PAS.0b013e31815701f3. - DOI - PMC - PubMed
    1. Tanaka M, Shibahara J, Fukushima N, Shinozaki A, Umeda M, Ishikawa S, Kokudo N, Fukayama M.. Claudin-18 is an early-stage marker of pancreatic carcinogenesis. J Histochem Cytochem. 2011. Oct;59(10):942–952. doi:10.1369/0022155411420569. - DOI - PMC - PubMed

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