ALX148

Background

Tumors evade destruction by the immune system by upregulating CD47, a marker of self, that functions as a myeloid immune checkpoint in cancer. By blocking the CD47-SIRPα pathway, it may be possible to enhance innate and adaptive immunity against cancer.1

ALX148

Figure 1.  ALX148 Structure

ALX Oncology’s fusion proteins are engineered to bind CD47 with significantly greater affinity than natural SIRPα. Our lead candidate, ALX148, is an intravenously administered fusion protein containing two engineered high affinity CD47 binding domains of SIRPα linked to an inactive Fc region of human immunoglobulin (Figure 1).2, 3

ALX148 Key Characteristics

  • ALX148 binds CD47 with high affinity and inhibits the CD47-SIRPα signaling pathway.
  • The Fc region of ALX148 is engineered to be inactive towards Fc gamma receptors, minimizing hematologic toxicity seen with other CD47 blockers.
  • The molecular weight of ALX148 is half that of an antibody, and thus is able to achieve linear pharmacokinetics and complete CD47 target occupancy at doses that are approximately half that of an anti-CD47 antibody.

In preclinical models, ALX148 blocks CD47 and safely enhances the activity of checkpoint inhibitors and anti-cancer targeted antibodies through Fc dependent and independent mechanisms. Thus ALX148 bridges innate and adaptive immunity to activate multiple immune cell types against tumors (Figure 2).2, 3

Figure 2.  ALX148 Mechanism of Actions

Macrophage phagocytosis is regulated by CD47-SIRPα signaling (an inhibitory signal) and Fc receptor engagement (a positive signal). The combination of ALX148 (blocking CD47) and anti-cancer antibodies (engaging Fc receptors) maximally activates macrophages to eliminate tumor cells.



ALX148 increases the ratio of inflammatory M1 tumor associated macrophages (TAMs) to suppressive M2 TAMs.



ALX148 activates dendritic cells (DCs) and enhances cross-priming of T cells, including CD8+ cytotoxic T cells.



References

  1. Weiskopf, K. Eur J Cancer. 2017 May;76:100-109.
  2. Kauder, S. et al. 59th Annual Meeting, American Society of Hematology 2017.
  3. Kauder, S. et al. Manuscript submitted.