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

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
• human CLDN18.2
• IMAB362
• immunotherapy
• RiboMab
• RNA therapeutics
• solid tumor
• Zolbetuximab

Acknowledgments

The authors would like to acknowledge Sandra Gandré for editorial, organizational, and writing support, Dr Philip Chang for critical review of the PK sections and Dr Andrew Finlayson and Dr Robert Wilson for an overall review of the manuscript.

Disclosure 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.

Data availability statement

Additional supporting data cannot be made publicly available due to a pending patent application but are available from the corresponding author upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2255041

Additional information

Funding

The work presented here was funded by BioNTech SE.