Angiex founder publishes paper describing the TM4SF1 intracellular transport pathway utilized by AGX101

07 May 2024

Angiex’s principal scientific founder, Shou-Ching S. Jaminet, and her collaborators Chi-Iou Lin and Anne Merley, published the paper TM4SF1 is a molecular facilitator that distributes cargo proteins intracellularly in endothelial cells in support of blood vessel formation in the May 7, 2024 edition of the Journal of Cell Communication and Signaling.

The paper describes TM4SF1’s function as an intracellular transporter of growth factor activated proteins in endothelial cells. By enabling endothelial cells to respond to growth factors and switch from a quiescent to an activated angiogenic state, TM4SF1 plays an essential role in angiogenesis and tumor growth.

The paper describes TM4SF1’s unique internalization route along microtubules from cell surface to nucleus (see image top).

Dr. Jaminet and her collaborators further show that TM4SF1-enriched microdomains transport a variety of growth factor activated proteins, including HDAC6, Akt, PLCγ, PKCα, MEK1/2, ERK1/2, and Rac1, from cell surface to nucleus. 

Figure 2A of the paper


Notably, Angiex’s lead drug, AGX101, binds to TM4SF1 and hitchhikes along this transport route, delivering its conjugated drug payload to the nucleus of cells in the tumor environment.

Other key findings of the paper:

  • Tumor growth and wound healing are both inhibited in Tm4sf1‐heterozygous mice, due to the reduced quantity of TM4SF1 protein.
  • A majority of growth factor activated signaling molecules examined are transported in endothelial cells by TM4SF1-enriched microdomains.
  • When TM4SF1 is knocked down, endothelial cells become unable to proliferate.

As this paper and related work by the same authors show, TM4SF1’s intracellular transport pathway is ideally suited to antibody-drug conjugate therapy for solid cancers. Three reasons:

  • As a pathway for the transport of growth factor activated proteins, TM4SF1 internalization is most active in growing tissues. In adults, the only growing tissues are tumors.
  • TM4SF1 internalizes to the nucleus, a uniquely attractive location for delivery of ADC payloads.
  • TM4SF1 is expressed and its internalization pathway is active in both tumor cells and tumor blood and lymph vessels, enabling TM4SF1-directed ADCs to attack multiple compartments of tumors.

Citation: Lin CI, Merley A, Jaminet SS. J Cell Commun Signal. 2024 May 7;18(2):e12031. DOI: 10.1002/ccs3.12031. eCollection 2024 Jun. PMID: 38946725.

Full text of the paper: PMC11208120.


About Angiex

Angiex Inc. is a privately held biotech startup whose mission is to exploit newly discovered biological transport mechanisms to make drugs with revolutionary power over cancer. Based in Cambridge, Mass., Angiex was founded by a scientific team of leading experts in angiogenesis, vascular biology, and oncology. The company is developing a novel portfolio of Nuclear-Delivered Antibody-Drug Conjugates™ (ND-ADCs) that release therapeutic payloads directly into the nucleus or cytosol, where the site of payload action is located. This direct delivery holds the promise of enhancing the efficacy and therapeutic margin of conventional ADCs. The lead product, AGX101, has advanced through pre-clinical development and is about to begin Phase 1 clinical trials. To learn more about Angiex...