In the Marvel Comic Universe, Venom is a superhero who started life as a supervillain and Spiderman foe.

In the biopharma universe, scorpion venom is undergoing the same fate transformation, as separate papers this week reported new ways to use scorpion venom in two major therapeutic targeting challenges.

Scientists at the Fred Hutchinson Cancer Research Center identified a class of scorpion venom miniproteins, the cystine-dense peptides (CDPs), that accumulated in cartilage, and could be used to deliver steroids specifically into joints in mice.

And investigators at the City of Hope used another scorpion venom peptide, chlorotoxin, as receptor in a CAR T cell that targeted glioblastoma.

Finding appropriately string and selective targets has been one of the major obstacles to moving CAR Ts into the solid tumor space.

A chlorotoxin CAR T cell interacting with a tumor cell. Nuclei are stained blue (big: tumor cell; small: T cell). The aggregation of yellow color at the interface between the two cells is the formation of immune synapse, a key indicator of T cell activation which will lead to tumor killing. Credit: City of Hope

Co-corresponding author Christine Brown, deputy director of the T-cell therapeutics research laboratory at City of Hope, said in a video interview that the goal of CAR T-cell receptors is to “target as large a proportion of tumor cells as possible,” a task at which the chlorotoxin-based receptor performed admirably.

The receptor was able to target tissue from “more patients, and more cells within those patients, than any other agent we’ve tried,” in orthotopic xenograft experiments, said Michael Barish, the professor and chair of the department of developmental and stem cell biology at the Beckman Research Institute of City of Hope.

Based on the results, Brown said, a clinical trial of the new CAR T “has just activated last week” and is currently screening patients.

Chlorotoxin is already being used to visualize brain cancers during surgery, with the goal of allowing surgeons to remove more tumor tissue while sparing healthy cells that are next to the tumors. As “tumor paint,” tozuleristide (BLZ-100, Blaze Bioscience Inc.) is in a phase II/III trial for pediatric brain cancer, and a phase I trial for adult glioblastoma.

Heather Franklin, Blaze president and CEO, told BioWorld that the chlorotoxin used by Blaze is a different variant from the one used in the CAR T work described by the City of Hope team, but that the company also has “preclinical work underway to use the power of chlorotoxin to direct therapeutics to tumors.”

The team is using the data from imaging studies with tumor paint as a guide for which tumors might be particularly susceptible to chlorotoxin-delivered therapeutics, and is considering brain cancers as well as breast cancers and sarcomas.

Heather Franklin, president and CEO, Blaze

Franklin said that “we have the ability with our technology to either make these synthetically,” which would lend itself to attaching small molecules, “… or express them recombinantly,” which could be used to make fusion proteins.

Blaze is a spinout from the lab of Fred Hutchinson Cancer Research Center’s James Olson, whose team published the arthritis work in the same issue of Science Translational Medicine.

Olson, who is a member of the clinical research division and Fred Hutch and an adjunct professor of pathology and pharmacology at the University of Washington School of Medicine, told BioWorld that finding proteins that would accumulate specifically in cartilage was unexpected.

“We were primarily looking for molecules other than chlorotoxin, the mini-protein that we use in Tumor Paint… that crossed into the brain. We indeed found some, but the real surprise was the other scorpion proteins that accumulated in joints,” he said.

Cartilage is avascular, that is, it lacks arteries and capillaries. “So most drugs fail to enter cartilage,” he said.

In the study published in Science Translational Medicine, Olson and his colleagues showed that CDPs accumulated in cartilage within half an hour of systemic administration, and remained detectable for several days. The team next linked the peptide to either an imaging agent or one of two steroids, dexamethasone or triamcinolone acetonide (TAA). While dexamethasone still had systemic toxicity when delivered via CDP, the TAA-CDP conjugate reduced joint inflammation in a rat model of arthritis, but did not show the sort of systemic toxicities that make steroids as hated as disease among many patients who must take them.

Accumulation of CDPs in the joint cartilage of mice. Credit: M.L. Cook-Sangar et al., Science Translational Medicine (2020)

CDPs and their ability to accumulate in cartilage, Franklin said, are the “lead out of a broad program” investigating the biodistribution of scorpion venom as well as other venoms and toxins from other species. Several of the paper’s co-authors are Blaze employees, and Blaze has “an ongoing collaborative relationship with the Hutch, and so we have option rights” to findings coming out of that program.

The company, she said, is “starting to talk to people about either partnering this program, or looking at a broader collaboration.”

Olson and his team, meanwhile, will “continue working on the arthritis program along with programs in other tissues that we will report when the data mature,” he said. It is likely that there will be other tissues, too, that can be specifically targeted by various venoms. But when asked which specific tissues, Olson said, “I think it's premature to answer that question beyond saying, ‘Yes, there are other important tissue types that I personally have high hopes for.’”

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