ONCOGENIC SIGNALING

The EGFR and MUC1 pathways

EGFR is a receptor tyrosine kinase that activates signaling pathways involved in cell proliferation and differentiation. MUC1 is a tumor-associated antigen that is hypoglycosylated in some cancer cells and colocalizes with EGFR as a result of loss of cell polarization.1-4

M1231 - MUC1xEGFR antibody-drug conjugate (ADC)

Description and Mechanism of Action:

M1231 is an investigational first-in-class, bispecific MUC1xEGFR ADC that delivers a cytotoxic hemiasterlin-related payload to tumor cells expressing MUC1 and EGFR, causing cell death through disruption of microtubule dynamics.4

Cooperative binding to MUC1 and EGFR promotes targeted delivery of M1231 to tumor cells and efficient internalization, thus potentially enhancing the antitumor activity of M1231 and minimizing its effect on normal cells. Targeting both MUC1 and EGFR may increase efficacy and reduce off-target effects compared with monospecific EGFR ADCs.4

The EGFR and MUCI Pathway

Areas of Interest:

TRIALS

M1231 in Participants With Solid Tumors5 (NCT04695847)

M1231 monotherapy is being investigated in a first-in-human, phase I, open-label study in patients with advanced solid tumors (dose escalation phase), and in patients with metastatic non-small cell lung cancer (NSCLC) expressing both MUC1 and EGFR, and in patients with metastatic esophageal squamous cell carcinoma (dose expansion phase).5

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Pathways Under Investigation

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Abbreviations:
EGFR, epidermal growth factor receptor; IAP, inhibitor of apoptosis; MET, mesenchymal epithelial transition factor; MUC1, mucin 1.

References:

  1. Engel BJ, Bowser JL, Broaddus RR, Carson DD. MUC1 stimulates EGFR expression and function in endometrial cancer. Oncotarget. 2016;7:32796-32809.
  2. Burke PA, Gregg JP, Bakhtiar B, et al. Characterization of MUC1 glycoprotein on prostate cancer for selection of targeting molecules. Int J Oncol. 2006;29:49-55.
  3. Piyush T, Chacko AR, Sindrewicz P, Hilkens J, Rhodes JM, Yu LG. Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells. Cell Death Differ. 2017;24:1937-1947.
  4. Knuehl C, Toleikis L, Anderl J, et al. M1231: a first-in-class bispecific antibody-drug conjugate targeting EGFR and MUC1. Presented at: American Association for Cancer Research Annual Meeting; June 24, 2020; Philadelphia, PA. Session MS.ET03.01.
  5. M1231 in participants with solid tumors. ClincalTrials.gov identifier: NCT04695847. Updated September 22, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/NCT04695847

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