Both approaches disrupt the same checkpoint, but with different safety profiles. Anti-CD47 antibodies (Magrolimab) block CD47 on all cells including RBCs, causing dose-dependent anemia that requires priming dose strategies. Anti-SIRPα antibodies target only SIRPα-expressing macrophages/DCs, avoiding RBC depletion. SIRPα-Fc decoy receptors (Evorpacept/ALX148) offer an alternative by competing with endogenous SIRPα for CD47 binding. The choice depends on the desired therapeutic window and combination strategy.

SIRPα is one of the most polymorphic receptors in the human immune system, with over 10 common allelic variants. The N-terminal IgV domain — the CD47-binding domain and therapeutic antibody target — shows the highest variability. Anti-SIRPα antibodies that bind only one variant may not cover the full patient population. Regulatory agencies expect cross-variant binding data. Testing candidates against a SIRPα variant panel (minimally V1, V2, and V8) is now standard practice in anti-SIRPα drug development.

Differentiate primary monocytes or THP-1 cells into macrophages (M-CSF, 7 days). Label target tumor cells with a fluorescent dye (CFSE or pHrodo). Pre-treat macrophages with anti-SIRPα blocking antibody (30 min), then co-culture with labeled tumor cells at a 1:5 E:T ratio (2-4 hours). Quantify phagocytosis by flow cytometry (% CD14⁺CFSE⁺ double-positive). For maximum effect, combine SIRPα blockade with a tumor-opsonizing antibody (e.g., anti-CD20 for lymphoma cells).

The SIRP family has three members. SIRPα (CD172a) is the inhibitory receptor — it binds CD47 and has ITIM motifs that suppress phagocytosis. SIRPβ (CD172b) is an activating receptor — it lacks ITIMs and instead associates with the adaptor DAP12/TYROBP to promote myeloid activation; SIRPβ does not bind CD47. SIRPγ (CD172g) is expressed on T cells, binds CD47 with low affinity, and may play a role in T-cell transendothelial migration. Only SIRPα is relevant to the CD47 "don't eat me" checkpoint.

Yes. SIRPα (CD172a) is widely used to identify monocytes, macrophages, and dendritic cell subsets. It is particularly useful for distinguishing cDC1 (SIRPα⁻/low) from cDC2 (SIRPα⁺) in human blood and tissue. In combination with CD11b, CD14, and HLA-DR, SIRPα helps define the full myeloid compartment in tumor immunophenotyping panels.