Discovery of novel cMET-targeting antibody Fab drug conjugates as potential treatment for solid tumors with highly expressed cMET

ABSTRACT

Background

Solid tumors are becoming prevalent affecting both old and young populations. Numerous solid tumors are associated with high cMET expression. The complexity of solid tumors combined with the highly interconnected nature of the cMET/HGF pathway with other cellular pathways make the pursuit of finding an effective treatment extremely challenging. The current standard of care for these malignancies is mostly small molecule-based chemotherapy. Antibody-based therapeutics as well as antibody drug conjugates are promising emerging classes against cMET-overexpressing solid tumors.

Research design and methods

In this study, we described the design, synthesis, in vitro and in vivo characterization of cMET-targeting Fab drug conjugates (FDCs) as an alternative therapeutic strategy. The format is comprised of a Fab conjugated to a potent cytotoxic drug via a cleavable linker employing lysine-based and cysteine-based conjugation chemistries.

Results

We found that the FDCs have potent anti-tumor efficacies in cancer cells with elevated overexpression of cMET. Moreover, they demonstrated a remarkable anti-tumor effect in a human gastric xenograft mouse model.

Conclusions

The FDC format has the potential to overcome some of the challenges presented by the other classes of therapeutics. This study highlights the promise of antibody fragment-based drug conjugate formats for the treatment of solid tumors.

KEYWORDS:

• Antibody fragment drug conjugate
• Fab-drug conjugate
• hepatocyte growth factor
• solid tumors
• c-Mesenchymal epithelial transition factor

Declaration of interest

All authors were employed by Sorrento Therapeutics, Inc. (STI) when their part of the study was conducted. All work was carried out in STI. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Y Fu, H Ji and G Kaufmann were involved in the conception. Y Fu, R Lim, M Buschman, H Zhou, J Chen and L Li were involved in study design and data interpretation. H Zhou carried out the phage display and SPR studies. A Khasanov and T Zhu synthesized all linker-payloads. R Lim, A Ledesma, J Niu and T Nguyen were involved in Fab generation, conjugation, purification, characterization studies. M Buschman, J Guo, RL and J Huang were involved in in vitro characterization experiments. J Chen, R Wang and L Li were involved in mouse in vivo study. L Kerwin carried out mAb production. Y Zhang carried out plasmid construction and optimization. Y Guo carried out the LC-MS analysis and co-wrote the methodology section. R Lim drafted the manuscript. J Huang assisted in the preparation of the manuscript. Y Fu, R Lim and L Li were involved in revising the manuscript.

Acknowledgments

We thank Ms. Elizabeth Orr for critical reading of the manuscript. M Buschman’s current affiliation is Janssen Research and Development. A Khasanov, J Niu, T Zhu, R Lim, L Kerwin, R Wang, L Li and J Chen are currently self-employed. A Ledesma’s current affiliation is QuidelOrtho. T Nguyen’s current affiliation is FormFactor Inc. J Guo’s current affiliation is Zentalis Pharmaceuticals. J Huang’s current affiliation is Boston University School of Public Health. Y Guo’s current affiliation is Arcturus Therapeutics. G Kaufmann’s current affiliation is Kyowa Kirin, Inc.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2023.2292633

Additional information

Funding

This paper was not funded.