Translation in Brief

IPD’s synthetic bio unlocks target combos for cell therapy; plus Merck’s oral STING agonist, Surrozen’s regenerative therapy and more

BioCentury’s roundup of translational news

BioCentury’s roundup of translational news.

Synthetic switches aim T cells at cells expressing antigen combos

David Baker’s team at University of Washington’s Institute for Protein Design published a study in Science showing its synthetic protein switches can direct T cells to kill target cells expressing precise combinations of cell surface antigens, opening the door to more selective targeting of tumor cells while sparing nearby healthy cells. Several of the authors listed as inventors on patents related to the switch technology, dubbed Co-LOCKR (Colocalization-dependent Latching Orthogonal Cage/Key pRoteins), hold equity in Lyell Immunopharma Inc., which Baker co-founded (see “IPD’s De Novo Revolution”).

Oral STING agonist for antitumor immunity without systemic toxicity

A Merck & Co. Inc. (NYSE:MRK) paper in Science describes a preclinical, orally bioavailable non-nucleotide STING agonist that could overcome the toxicity risk that has limited the compound class to intratumoral delivery. The compound was well-tolerated, induced tumor regression and protected from tumor re-challenge in a syngeneic mouse model of colon cancer. Structural and modeling studies suggest the small molecule, which predominantly exists as a monomer, only binds STING in its dimeric form, which is selectively concentrated in acidic tumor environments. 

In the same issue of Science, a Scripps Research team described a different oral small molecule STING agonist that was identified via a phenotypic screen and showed antitumor activity. The Scripps compound acts as a mimetic of the natural STING activator cGAMP.

Surrozen’s bispecific Wnt modulator

Researchers from Surrozen Inc. published data in Scientific Reports showing its tissue-specific R-spondin mimetic enhances Wnt3a signaling and stimulates cell proliferation, specifically in the liver. The bispecific antibody targets a liver-specific receptor, ASGR1, and administration of the molecule improved liver function in diseased mice. The company is working on several other targeted therapies using its regenerative antibody platform (see “Selective Regeneration”).

Extrachromosomal DNA associated with poor cancer outcomes

A team led by Boundless Bio scientists performed whole-genome sequencing of 3,212 cancer patients and found high levels of extrachromosomal DNA (ecDNA) that resulted in increased levels of oncogene transcription and a decreased survival rate. Reported in Nature Genetics, the researchers found that 460 (14%) tumor samples had ecDNA-based amplification across 25 out of the 29 cancer types analyzed. Boundless is developing small molecules to destroy cancer cells that depend on ecDNA (see “Boundless Bio”).

Gladstone team analyzes T cells of recovered COVID-19 patients

A Gladstone Institutes team led by Nadia Roan, a professor at the University of California San Francisco published an overview in Cell Reports Medicine of the characteristics of CD4+ and CD8+ T cells found in nine patients who had recovered from mild cases of COVID-19. The researchers found that a large proportion of the SARS-CoV-2-specific T cells expressed a surface protein known to mark long-lived cells, and were found in patients more than two months after infection, supporting the role of T cells in conferring long-term immunity against SARS-CoV-2. 

TARGETS
ASGR1 (ASGPR; CLEC4H1) – Asialoglycoprotein receptor 1 
LGR5 (GPR49) – Leucine-rich repeat-containing G protein-coupled receptor 5
RNF43 – Ring finger protein 43  
RSPO2 – R-Spondin 2 
WNT3A – Wingless-type MMTV integration site family member 3A 
ZNRF3 – Zinc and ring finger 3