August 2022 – Walking Fish Therapeutics was named after the Axolotl, a small amphibian that can regenerate lost limbs and even a damaged heart. The company's co-founder, chairman and CEO, Rusty Williams, MD, PhD, has long marveled at this capacity and draws on it for inspiration.

Like Axolotl, Walking Fish is keen to regenerate biological systems, such as reconstituting the body's immune response against tumors or supplying lost enzymes. To get there, the company is harnessing patients' B cells and giving them new capabilities.

“About 20 years ago, a few colleagues and I had the idea that we could engineer cells to produce a therapeutic protein and reintroduce those cells into the body,” said Williams. “That could provide a steady production for a therapeutic protein, and the patient would not have to come back repeatedly for more infusions.”

B cells are ideal protein-making factories because they already know how to do it – their day job is producing antibodies. In addition, B cells differentiate into plasma cells, which can stay in the body for years or even decades.

“This idea that we could infuse these long-lasting, therapeutic protein factories into patients captured our imagination,” said Alexis Ji, Venture Partner at Illumina Ventures. “Rather than patients going to the clinic over and over, the treatment is always there. This creates the potential to offer functional cures for serious diseases.”

​

Regenerating Immune Responses Against Cancer

Immunotherapies are revolutionizing cancer care, but they often fall short. Checkpoint inhibitors release the brakes on immune cells but only work for a relatively small group of patients. CAR-T therapies engineer T cells to target a common tumor antigen but potentially have high toxicity and are ineffective against solid tumors.

​

Walking Fish believes B cells offer a solution. Like dendritic cells, B cells are good at presenting antigens; however, they are much easier to extract from blood.

​

By engineering a patient's own B cells to recognize cancer antigens and reinfusing those cells, the company hopes to stimulate the immune system to recognize abnormal tumor proteins and target them. Even better, this approach works in solid tumors and could possibly prevent recurrence.

​

“CAR-T cells directly kill tumor cells, but they don't generate any immune system memory,"” said Williams. “Our goal is to trigger a long-lived immune response to the cancer.”

The Challenges of Engineering B Cells

Researchers initially focused on T cells as potential therapies because they're much easier to engineer than B cells. Walking Fish is taking the road less traveled and has achieved some significant milestones: perfecting technologies to expand B cells from patient blood; engineering them to produce therapeutic proteins; and differentiating them into long-lasting plasma cells.

​

In addition, while regular B cells are exceptionally good at producing antibodies, Walking Fish B cells have a much broader repertoire.

​

“With gene editing technologies, we can engineer B cells to express other proteins beyond antibodies,” said Williams. “We can use this cellular machinery to make robust amounts of therapeutic proteins.”

​

Cancer and Rare Diseases

In oncology, Walking Fish is first targeting solid tumors. On the protein replacement side, the company wants to treat rare, debilitating and painful congenital diseases, such as lysosomal storage disorders.

​

These conditions are caused by mutations in an enzyme that helps make up lysosomes, a type of cellular garbage truck. Reduced garbage pickup allows toxic material to build up in cells, affecting skin, heart, kidney, brain and other tissues.

​

Walking Fish is developing B cells that restore this enzyme, which could alleviate these symptoms indefinitely.

​

“We've engineered B cells to produce this missing protein,” said Williams. “Now, our goal is to extract a patient's own B cells, engineer them to produce the enzyme and readminister them.”

The Ultimate Combination

Walking Fish is also working to combine two B cell attributes into one therapy: producing therapeutic proteins and hitting specific targets. “We are combining these two platforms, designing a B cell that delivers a therapeutic protein and can home in on diseased tissue,” said Williams.

This strategy could help treat heart disease, as engineered B cells could ferry anti-inflammatory proteins directly to the heart. And because this therapeutic approach would be highly localized, it could be delivered with minimal side effects.

“We're learning from these two parallel approaches that, in the long term, we may be able to use B cells as factories that go directly to diseased tissues and locally produce needed proteins,” said Williams. “That's a major paradigm shift in medical therapeutics.”

​

​

To learn more, visit https://www.walkingfishtx.com/.