Latest preclinical data support promise of CAR-M cell therapy LIB820

Liberate Bio’s investigational CAR-M cell therapy LIB820 may help successfully eliminate disease-driving B-cells in autoimmune diseases such as multiple sclerosis (MS) without causing severe side effects, according to new preclinical data.

The therapy is designed to genetically engineer two types of immune cells — monocytes and macrophages — within the patient’s body (in vivo) to specifically target and eliminate B cells. This approach differs from more conventional CAR T-cell therapies, which instead modify immune T-cells and have been linked to severe inflammatory side effects and neurotoxicity.

In line with previous results showing nearly complete elimination of B-cells in nonhuman primates upon treatment, the new data further support the ability of these engineered immune cells to drive B-cell depletion with no evidence of side effects commonly associated with CAR T-cell therapies.

The findings, presented last week at the American Society of Gene and Cell Therapies annual meeting in Boston, support plans to launch an investigator-initiated clinical trial in diffuse cutaneous systemic sclerosis, an autoimmune disease also driven by B-cell activity, that’s expected to begin by the end of the year.

But according to the company, the initial clinical focus will also include MS and lupus, another autoimmune disease.

“We’re excited by the fact that this is a novel approach to target B-cells with a CAR – one that doesn’t require expressing CAR in T-cells,” Walter R. Strapps, PhD, Liberate’s chief scientific officer, who presented the data at the conference, said in a company press release.

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CAR T-cell therapies, which harness the activity of immune T-cells to recognize and destroy threats, have emerged as a potential strategy to eliminate B-cells, which are involved in a variety of autoimmune conditions such as MS.

Traditionally, the approach involves collecting T-cells from a patient or donor and modifying them in the lab to produce a chimeric antigen receptor (CAR) that will recognize a protein on the surface of B-cells. The engineered cells are then infused into a patient, where they seek out and destroy B-cells.

But producing these therapies can take several weeks, be costly, and often requires chemotherapy beforehand to prepare the body to receive the modified cells.

Newer in vivo CAR T-cell therapies, which genetically modify T-cells directly inside the patient’s body, have been explored to overcome these challenges. However, CAR T-cell therapies remain associated with concerns about serious side effects, including cytokine release syndrome (CRS), a potentially life-threatening inflammatory reaction, and neurotoxicity linked to excessive T-cell activation.

“The field has seen the promise of in vivo CAR-T and the potential to broaden access to this important class of therapeutics, but T-cell programming is not the only path to immune reset,” said Shawn P. Davis, PhD, Liberate’s CEO.

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LIB820 led to a more than 99% depletion of B-cells in previous studies

LIB820 is designed to take a different approach by harnessing monocytes and macrophages, which engulf and clear harmful substances, to go after B-cells.

The therapy uses tiny fat-based particles called lipid nanoparticles (LNPs) to target these immune cells specifically. Inside the LNPs is a messenger RNA (mRNA) molecule that contains instructions to produce a CAR targeting the CD19 protein on B-cells. mRNA is a temporary molecule used as a blueprint to make proteins.

“LIB820 is designed to harness monocytes and macrophages as programmable effector cells — delivering cell-therapy-like activity through a repeatable, off-the-shelf medicine while avoiding the T-cell activation biology associated with cytokine release syndrome and neurotoxicity,” Davis said.

In previous studies, Liberate used its proprietary RAPTOR platform to screen multiple LNPs in nonhuman primates. After two well-tolerated doses, the lead nanoparticle resulted in more than 99% depletion of B cells.

LIB820 is designed to harness monocytes and macrophages as programmable effector cells — delivering cell-therapy-like activity through a repeatable, off-the-shelf medicine while avoiding the T-cell activation biology associated with cytokine release syndrome and neurotoxicity.

While temporary increases in certain inflammatory molecules, also called cytokines, were observed after each dose, these returned to normal within two days. Fewer than 1% of T-cells were reached by the therapy.

The newly presented findings expand on those earlier results across additional cell systems and animal models, while further supporting the therapy’s favorable tolerability profile, according to Liberate.

“We’ve made great strides over the last six months on demonstrating the robustness of our novel LNP,” said Strapps. “We’re able to demonstrate that CAR-expressing myeloid cells can act as effector cells to deplete B-cells in circulation, and we see no evidence of the cytokine spikes that likely drive CRS.”

Liberate is now running studies to test whether dosing adjustments may help prolong the therapy’s activity and improve its ability to reach disease-relevant tissues. Updated data are expected later this year.

The company is also exploring the broader potential of its in vivo CAR-M platform in other diseases, including multiple myeloma, a B-cell blood cancer.