Nearly a year after making cell therapy history by dosing the first patient with the first engineered B cell in a human trial, Immusoft has reported promising but early clinical data showing its lead candidate was effective nine months after dosing, as well as safe.
Immusoft has presented data from its Phase I trial (NCT05682144) assessing ISP-001 nine months after administering a single low dose of 2.5 x 107 cells/kg in a patient with mucopolysaccharidosis type I (MPS I). The data showed the patient—identified as a man in his mid-20s—to have pharmacodynamic, functional, reported quality of life, and daily living activity improvements, as well as reduced pain associated with MPS I.
“We really weren’t sure that we would see anything in the way of efficacy. And that’s for two reasons: One, it was a low dose, and two, it was an adult patient. And the belief is that in adults, once these manifestations are set in, they’re not reversible,” Immusoft CEO Sean Ainsworth said.
“To our delight, we actually saw reversal of some of these manifestations. So considering that it’s at the low dose, we were quite astonished and pleasantly surprised,” Ainsworth said. “It has been really extraordinary.”
Even better for the patient, Ainsworth said, ISP-001 requires no preconditioning regimen—an advantage to ISP-001 that Immusoft has promoted at a time when researchers across industry and academia seek less toxic alternatives to busulfan as a bone conditioning regimen, a crucial component of cell and gene therapy protocols.
Immusoft has reported ISP-001 to be well-tolerated, with no adverse events reported at the data cutoff date of September 24, and as of October 9 when Ainsworth spoke with GEN Edge.
ISP-001 is the first product candidate developed by Immusoft using its Immune System Programming (ISP
) tech platform, designed to modify a patient’s B cells and instruct those cells to produce gene-encoded medicines.
Hybrid approach
ISP is a hybrid cell/gene therapy approach that uses a clinically validated, non-viral vector designed to deliver functional genes into immune cells using DNA rather than a virus through the Sleeping Beauty (SB) Transposon System. Immusoft acquired the system when it bought Discovery Genomics in 2016 for an undisclosed price, gaining a license to use Sleeping Beauty for MPS I plus options to license the platform for hemophilia and inherited lysosomal storage disorders.
ISP collects blood from patients via apheresis to obtain B cells, which according to Immusoft are ideal for modifying because of their protein-producing capabilities. The B cells are selected and purified for reprogramming and differentiation.
Using a non-viral gene delivery system of autologous plasmablasts engineered to express α-L-iduronidase (IDUA), the B cells are programmed with DNA to enable them to produce large amounts of therapeutic protein. The B cells respond by becoming miniature protein therapeutic “biofactories” or plasma cells that manufacture and secrete thousands of antibodies per second. The ISP-programmed cells are then infused back into the patient, where they produce therapeutic proteins for extended periods of time.
How long can they last? “We expect many years of protein expression,” Ainsworth replied, though how long remains under study—and if needed, the treatment can be redosed.
Immusoft looks at vaccines as a proxy for what it’s trying to accomplish via cell therapy—especially when it comes to not needing preconditioning.
“B cells, naturally, once they recognize that vaccine, they differentiate into plasma cells. Those the biofactories. They migrate naturally to the bone marrow and take up residence and engraft. That’s where they live for decades and produce therapeutic antibody over decades,” Ainsworth explained. “In our case, we’re emulating that, but instead of giving a vaccine, we activate (the B cells) ex vivo and differentiate them towards the plasma cell. That’s what we deliver back to the patient. And that’s what then migrates to the bone marrow. No need for any myeloablation.”
The clinical study had two parts. In the first, the patient was treated with ISP-001 and the enzyme replacement therapy Aldurazyme® (laronidase), marketed by Sanofi. The patient had been receiving Aldurazyme for 10 years. In the second, ERT was ended and the patient was treated with ISP-001 alone.
Functional improvements
For that first patient, Immusoft reported a series of functional improvements as ISP-001 broke down the glycosaminoglycans or GAGs built up in tissues and organs, as measured in the urine. Following the combination of ISP-001 and Aldurazyme, the patient’s urinary GAG level dropped from 39.5 mg/mmol creatine pre-diagnosis before receiving Aldurazyme, to a 6.9 mg/mmol baseline at the start of treatment with Aldurazyme and ISP-001, to 4.3 mg/mmol eight months later, within normal range.
Immusoft contrasts those findings with a disclosure on Aldurazyme’s prescribing information sharing results from a Phase III 26-week placebo-controlled study in 45 patients (NCT00912925): “No patient in the group receiving Aldurazyme reached the normal range for urinary GAG levels.”
At six months, the patient showed 107-meter improvement in both a six-minute walk test (6MWT) and a 17-degree improvement in shoulder flexion—compared with 20-meter and 10-degree improvements in the pivotal trial used for approving Aldurazyme.
For the final month of ISP-001 monotherapy, urinary GAG level rose to 11.2 mg/mmol in the ninth month, while improvements in functional activity persisted, according to Immusoft.
“We view this as pretty compelling early data for not just the MPS I program but for our platform, more broadly speaking,” Ainsworth said in an October 14 webinar at which he and chief medical officer Robert Sikorsky, MD, PhD, presented the data on ISP-001.
Future studies of ISP-001 will evaluate higher doses, Ainsworth said: “We have seen a dose response curve in animals, so we do expect that as we dose escalate in humans, that we will see a dose response in patients as well.”
Competing developers
Immusoft is among several companies competing to develop B cell-based cell therapies.
Another such company, Be Biopharma, aims to produce long-lasting production of therapeutic proteins through its platform that produces engineered B Cell Medicines (BCMs), with an initial focus on rare disease and oncology. Last month at the American Society for Bone and Mineral Research (ASBMR) 2024 Annual Meeting, Be Biopharma announced positive preclinical data showing its BCMs produced active alkaline phosphatase (ALP), highlighting their ability to potential treat Hypophosphatasia (HPP).
Unlike Immusoft, Be Biopharma uses CRISPR/Cas9 precision genome engineering of circulating B cells to insert a gene into an exact chromosomal location. By swapping in different genes of interest, the company says, it can create new product candidates for multiple diseases.
Be Biopharma then expands the engineered B cells, which differentiate into plasma cells that secrete the desired therapeutic protein following a change in culture conditions. Be says its platform can also produce thousands of antibodies per cell every second. Upon infusion into patients, the plasma cells migrate to the bone marrow to produce a desired therapeutic protein at constant levels. Because they are terminally differentiated and thus better to evade immune detection, Be says its BCMs allow for both controlled and repeat dosing.
Another developer of B cell therapies, Walking Fish Therapeutics, had worked in recent years to advance a pipeline of B cell therapies in oncology, rare disease, regenerative medicine, autoimmune disease, and recombinant antibody production.
Walking Fish completed an oversubscribed $73 million Series A financing in February 2022. But in May, Walking Fish shut down and auctioned off its lab equipment within two months of seeking clearance for a clinical trial of its Fabry disease program, after a lead investor backed off earlier plans to anchor a Series B financing, CEO Rusty Williams, MD, PhD, said in published reports.
Immusoft’s Phase I trial was funded through an $8 million Clinical Trial Stage Projects grant from the California Institute for Regenerative Medicine (CIRM). The grant accounts for most of the approximately $12 million in total funding Immusoft has received from CIRM, the state’s regenerative medicine agency funded with $5.5 billion in bonds approved by voters in 2020 and $3 billion in 2004.
Developing MPS II candidate
The other nearly $4 million ($3,994,676) was awarded through CIRM’s Therapeutics Translational Research Projects grant program to fund development of ISP-002, a treatment for MPS II, in which a patient’s own B cells are engineered to express iduronate 2-sulfatase (IDS), which prevents accumulation of glycosaminoglycans in various tissue. The cells are placed back into the patient where they secrete the IDS at a therapeutic level.
ISP-002 is in the Investigational New Drug (IND)-enabling phase, with Immusoft expecting to file an IND application in late 2025 or early 2026 Ainsworth said.
The rest of Immusoft’s pipeline consists of five programs in varying preclinical discovery phases—one each in Parkinson’s disease, Gaucher disease, and unspecified indications in oncology, autoimmune, and obesity/diabetes.
In obesity/diabetes, Immusoft aims to improve upon the glucagon-like peptide 1 (GLP-1) receptor drugs of Novo Nordisk and Eli Lilly that have revolutionized the metabolic disorder therapeutic area with blockbuster sales exceeding $1 billion annually. Novo Nordisk markets semaglutide as Wegovy® (in obesity) and Ozempic® (in type 2 diabetes), while Lilly markets tirzepatide as Mounjaro® (type 2 diabetes) and Zepbound® (obesity).
Ainsworth said Immusoft is looking to deploy a GLP from the B-cells it engineers, with an eye to creating muscle preserving treatments that avoid the muscle loss associated with the blockbuster drugs, while potentially gaining muscle function, and improving glucose control.
Based in Seattle, Immusoft was founded in 2009 by Matthew Scholz, who served as CEO through 2017 and is now a board member. Scholz conceived how a research system developed by Nobel Laureate David Baltimore, PhD, could be modified to program resting B cells to secrete therapeutic proteins. Scholz negotiated an exclusive license to the system, then developed and patented a way to improve its efficiency toward clinical viability. The modified system remains the core of Immusoft’s technology platform.
Immusoft employs 13 full-time equivalent staffers. Over the next year, Ainsworth said, “I think we’ll probably about double that, and maybe more.”
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