ALX148

Scientific Background

CD47 is a widely expressed protein on the cell’s surface and is often upregulated in cancer. CD47 functions as a ligand for signal regulatory protein-α (SIRPα), a transmembrane receptor on macrophages that inhibits macrophages from destroying cancer cells when bound to CD47.1 Thus CD47-SIRPα interaction is a key immune checkpoint mechanism exploited by cancer cells to evade the immune system.2

Anticancer antibodies represent important treatment options for patients with a broad range of cancer types; however, limited response rates and eventual cancer recurrence underscore the need for novel treatment approaches. Our strategy to block the CD47-SIRPα signaling cascade removes the inhibitory signal to macrophages, potentially improving the efficacy of anticancer antibodies while minimizing unwanted on-target toxicity.

ALX148

Figure 1.  ALX148 Structure

Alexo’s fusion proteins are engineered to bind CD47 with significantly greater affinity than natural SIRPα.3 Our lead candidate, ALX148, is comprised of two high affinity CD47 binding domains of SIRPα linked to an inactive Fc region of human immunoglobulin (Figure 1). ALX148 potently binds CD47 and inhibits the CD47-SIRPα signaling cascade. The engineered Fc region is inactive towards Fc receptors while maintaining its ability to prolong circulating levels of ALX148 in the body. These properties enable sustained blockade of CD47 without on-target phagocytosis of healthy cells.

The goal of Alexo’s approach of targeting the CD47 pathway using ALX148 is to selectively eliminate tumor cells (Figure 2) while avoiding the dose-limiting toxicities that have been seen with other CD47-targeted approaches in the clinic.

ALX148 is currently being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors and lymphoma; for more information, please visit clinicaltrials.gov, identifier number NCT03013218.

Figure 2.  Scientific Hypothesis

  1. In the basal state, CD47 on cancer cells binds SIRPα on macrophages and inhibits phagocytosis.

  2. Addition of ALX148 blocks CD47-SIRPα interaction, which removes the inhibitory signal and sensitizes macrophages.

  3. Treatment with anticancer antibodies alone stimulates modest phagocytosis via antibody binding to both Fc receptors on macrophages and tumor antigens on cancer cells.

  4. Addition of ALX148 in combination with anticancer antibodies maximizes phagocytosis of cancer cells.


 


References

  1. Stephen B. Willingham, et al. PNAS 109, 17 (2012); DOI: 10.1073/pnas.1121623109; Abstract link
  2. Robert H. Vonderheide. Nat Med 21, 10 (2015); DOI:10.1038/nm.3965; Abstract link: Abstract link
  3. Kipp Weiskopf, et al. Science 341, 88 (2013); DOI: 10.1126/science.1238856; Abstract link: Abstract link