Biopharmaceutical company Cabaletta Bio recently raised $38 million to develop treatments similar to CAR-T therapies for autoimmune diseases. The company has plans to file the treatment for Investigational New Drug status from the FDA in late 2019.
Cabaletta is a Pennsylvania-based company that is the product of research at the University of Pennsylvania. This Thursday, the pharma company announced they had raised $38 million in Series A funding, as well as an exclusive license agreement and two research agreements with the University of Pennsylvania. Their research involves discovery and development of chimeric autoantibody receptor T-cell, or CAAR-T therapies, for autoimmune diseases.
CAAR-T cells differ from CAR-T cells in that the engineered T cells contain antibody fragments that allow them to carry antigens targeted by B cells that cause autoimmune diseases, said Cabaletta co-founder and CEO Dr. Steven Nichtberger. CAR-T and CAAR-T therapies are similar in that they use a costimulatory domain called 4-1BB to increase cytokine production and a CD3-zeta signaling domain that mediates signaling during T-Cell activation.
“Instead of having fragments of the antibody to CD19 on the outside, instead of using those as a means of attracting B cells that express CD19, the antibody-antigen interaction is being flipped in our technology,” he said. CD19 is an antigen expressed by B cells and is targeted by Kymriah in its approved indications of pediatric ALL and adult diffuse large B-cell lymphoma. With CAAR-T, the B cells will attempt to attack the engineered T cells, which will respond by killing them.”
The funding round was led by 5AM Ventures, with founding investors Adage Capital Management and the University of Pennsylvania also participating. Penn also played a key role in the development of Novartis’ Kymriah, the first CAR-T drug to be marketed. This drug was approved last August by the FDA for treatment of pediatric leukemia.
Specifically, Cabaletta will initially focus on mucosal pemphigus vulgaris (mPV), an autoimmune disease that is estimated to affect one in every 2,630 people. Their leading product will be designed to eradicate B cells that produce antibodies to a target called desmoglein 3 (DSG3).
However, Nichtberger said another key difference is that because of how they work, CAAR-Ts will likely eliminate only 1 percent of normal B cells, while CAR-Ts eliminate all B cells, healthy and malignant. That condition, known as B-cell aplasia, results from the CAR-Ts targeting CD19, which occurs on normal and cancerous B cells.
It is also unlikely that the CAAR-Ts will cause cytokine release syndrome, or CRS, a potentially fatal side effect associated with CAR-Ts. Nichtberger said this is because CRS is associated with tumor burden in cancer patients, whereas the CAAR-Ts do not target tumors. Less certain is whether the CAAR-Ts will overcome another, also dangerous side effect of CAR-Ts, which is neurotoxicity, given that there are no widely accepted correlates for it. Nichtberger claims another key difference between the two is that CAAR-T treatments only eliminate 1% of normal B cells, whereas traditional CAR-T therapy eliminates all B cells, regardless of whether or not they are malignant. The condition in which too many B cells are eliminated is known as B-cell aplasia, and results from CAR-T targeting CD19, a factor contained by all B cells.
He claims that the CAAR-T therapy will be unlikely to cause a fatal side effect of cytokine release syndrome (CRS), common to CAR-T therapy. Nichtberger claims this is because CRS is coupled with tumor burden, while CAAR-T treatments won’t target tumors. Whether or not these new treatments will be able to overcome neurotoxicity, another dangerous side effect of CAR-Ts.
“I can’t tell you what the risk will be, and we’ll run the trial and see,” said Nichtberger.
Upenn spinout company Cabaletta Bio to commercialize CAR-T for autoimmune diseases @BLLPHD the first product candidate DSG3-CAART to be tested in pemphigus vulgaris https://t.co/Rkg8Yl2qh5 …
— Alexey Bersenev (@cells_nnm) November 8, 2018
Source: MedCityNews
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