South San Francisco-based clinical-stage biotechnology company Sutro Biopharma has received a milestone payment under its collaboration and license agreement with the healthcare division of Merck KGaA, Darmstadt, Germany.

The novel agent is being developed for the treatment of adult patients with metastatic solid tumors, including non-small cell lung cancer (NSCLC) and esophageal squamous cell carcinoma. The milestone payment is related to Sutro completing patient enrollment in the Phase 1 dose-escalation and expansion study of M1231, a first-in-class investigational bispecific antibody-drug conjugate targeting MUC1-EGFR.

Study design
The Phase 1 study is designed to establish a safe and tolerable dose and to investigate the pharmacokinetics and the first clinical efficacy signals of M1231 as a single agent in participants with solid tumors (Part 1) and with metastatic Non-small Cell Lung Cancer (NSCLC) and esophageal squamous cell carcinoma (Part 2). Dose escalation will be followed by the dose expansion once the maximum tolerated dose (MTD) or recommended dose for expansion (RDE) has been defined.

Targets
The investigational ADC targets MUC1-EGFR. MUC1 (transmembrane glycoprotein Mucin 1), is aberrantly glycosylated. It is overexpressed in a variety of epithelial cancers and plays a crucial role in the progression of the disease. Research has shown that tumor-associated MUC1 differs from the MUC1 expressed in normal, healthy, cells with regard to its biochemical features, cellular distribution, and function. In healthy cells, MUC1 provides protection to the underlying epithelia. In contrast, in cancer cells, MUC1 participates in intracellular signal transduction pathways and regulates the expression of its target genes at both the transcriptional and post-transcriptional levels.[1]

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Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that drives cellular processes including proliferation, migration, and survival. Scientists believe that MUC1 driven EGFR regulation occurs in endometrial cancers by elevating EGFR levels transcriptionally and by enhancing EGFR signaling. Based on this observation, they conclude that it may be possible that MUC1 and EGFR targeted co-therapies may provide a new avenue for the treatment of advanced endometrial cancer.[2]

Unmet medical needs
“The robustness and flexibility of our cell-free platform and our wholly-owned manufacturing facility have enabled the discovery and early clinical supply of M1231,” said Bill Newell, Chief Executive Officer of Sutro.

“The continuing progress of the program is indicative of the commitment both parties have made to drive the development of M1231 and represents an important achievement in the work of the collaboration to address unmet medical needs of cancer patients,” Newell added.

“This partnership demonstrates the combined strength of Sutro and Merck to expand the boundaries of antibody-drug conjugate. M1231 is a first-in-class investigational bispecific ADC. By targeting both MUC1 and EGFR, M1231 could potentially increase tumor selectivity, payload delivery, and reduce on-target toxicity on normal tissues,” explained Trevor Hallam, Ph.D., Sutro’s President of Research and Chief Scientific Officer.

Platform technology
M1231 was generated using Sutro’s XpressCF® and Sutro’s XpressCF+™ cell-free protein synthesis and conjugation technologies and includes a Sutro proprietary linker-payload. The ADC is based on Merck’s strand-exchange engineered domain (SEED) antibody platform.

Merck’s SEED platform was designed to generate asymmetric and bispecific antibody-like molecules, a capability that expands therapeutic applications of natural antibodies. This protein-engineered platform is based on exchanging structurally related sequences of immunoglobulin within the conserved CH3 domains and expands therapeutic applications of natural antibodies by generating heterodimeric Fc-analog proteins.[3]

Sutro’s XpressCF® platform is made possible by the separation, into an extract, of the cellular components required to produce proteins from the process of protein generation itself. The extract includes all the necessary biochemical components for energy production, transcription and translation and can be used to support cell-free biochemical protein synthesis by the addition of the specific DNA sequence for the desired protein.

Agreement
As part of the agreement, Sutro is manufacturing the antibody and linker-payload for the early clinical supply and is eligible for further payments and tiered royalties ranging from low to mid-single-digit percentages, along with certain additional one-time royalties, on worldwide sales of any commercial products that may result from the collaboration. Merck will be responsible for the drug product, clinical development, and, upon regulatory approval, the commercialization of this product candidate.

Clinical trials
M1231 in Participants With Solid Tumors – NCT04695847

Reference
[1] Nath S, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014 Jun;20(6):332-42. doi: 10.1016/j.molmed.2014.02.007. Epub 2014 Mar 22. PMID: 24667139; PMCID: PMC5500204.
[2] Engel BJ, Bowser JL, Broaddus RR, Carson DD. MUC1 stimulates EGFR expression and function in endometrial cancer. Oncotarget. 2016 May 31;7(22):32796-809. doi: 10.18632/oncotarget.8743. PMID: 27092881; PMCID: PMC5078052.
[3] Davis JH, Aperlo C, Li Y, Kurosawa E, Lan Y, Lo KM, Huston JS. SEEDbodies: fusion proteins based on strand-exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies. Protein Eng Des Sel. 2010 Apr;23(4):195-202. doi: 10.1093/protein/gzp094. Epub 2010 Feb 4. PMID: 20299542.

Featured image: Research laboratory. Photo courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.

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