Mechanistically, aPD1-S was shown to enhance M1 Mac abundance and preserve CD8 T cell function, as determined measuring markers of T cell exhaustion and stemness. These findings agree with work by Laubli et al., underscoring a through-line of myeloid inflammation that is potentiated by sialidase!

Finally, we put aPD1-S to the test in mouse melanoma models that (i) have poor responses to PD1 blockade and (ii) respond to sialic acid minimizing therapies. Relative to aPD1 or non-targeted sialidase, aPD1-S showed significant tumor control and increased survival, highlighting its future potential

We next put aPD1-S to the test using the LCMV model of CD8 T cell exhaustion, demonstrating PD1-targeted sialidase enhances (i) cytokine production and (ii) tumor cytolysis by otherwise hypofunctional ("exhausted"), CD8 T cells that are LCMV antigen-specific.

We similarly observed robust sialic acid removal from tumor-infiltrating T cells (shown in red)..and surprisingly.. from nearby tumor cells. We reasoned this off-target activity derived from the highly active S. typhumurium sialidase, and we made a less active variant to protect PD1(-) cells

We next evaluated the ability of aPD1-S to degrade sialic acids on PD1+ T cells in mixed cell assays, containing WT (PD1-) and GFP+PD1+ T cells. These experiments revealed aPD1-S to degrade sialoglycans from PD1+ T cells with ≥1000-fold selectivity, highlighting the utility of anti-PD1-targeting 🎯

To construct anti-PD1-sialidase (aPD1-S), we employed the transpeptidase Sortase A, and demonstrated the site-selective conjugates retain (i) PD1 binding and (ii) sialidase activity

so we wondered... what if we targeted immune cells directly? We reasoned delivering sialidase to T cells could maximize the neuraminidase effect where it matters most - at the immune synapse! And what better way to deliver sialidase than by piggybacking on approved anti-PD1 mAbs (a one-two punch 👊)

The Neuraminidase Effect, describes how removing sialic acids from T cells or APCs enhances T cell activation. How? There are several reasons... We think it enhances synapse formation (and) reinforces CD28-B7 binding, the critical costimulatory handshake needed for full T cell activation. 🤝

Accordingly, strategies targeting sialic acids in the #TME have emerged. Among these, tumor-targeted sialidases, first reported by @carolynbertozzi.bskyverified.social et al. - have shown major benefit for their ability to degrade tumor cell surface sialoglycans and potentiate immune responses

Tumors evade immune responses by coating themselves in a dense layer of sugars called sialic acids. These sugars broadcast a signal of "self" to the immune system, recruiting inhibitory #Siglecs, and sweet-talking their way out of immune detection

Osaka 2025

That’s all, folks!

Showing off some Paulson lab bling gifted to recent graduates! 🎓 ♦️ 💎

#Siglec #SialicAcid #Glycotime #PhD

Dear friends

I will defend my PhD Dissertaion on May15 at 14:00 PST.

Tune in to learn all about “Therpeutic Sialidase Conjugates Targeting the Glyco-Immune Axis in Cancer”.

(Link in the comments)

#Siglec #SialicAcid #Glycotime

View from the office today 🌈
Someone needs to check the hole on the 8th green..