The first two approved CAR-T therapies for blood cancers have already been on the market for more than a year, and additional products are on the way. But a new company is fixing to take the cell therapies out of their hematological silo.

Radnor, Pennsylvania-based Cabaletta Bio, spun out from research at the University of Pennsylvania, announced its launch Thursday with a $38 million Series A funding round, along with an exclusive license agreement and two multi-year research agreements with the university to discovery and develop chimeric autoantibody receptor T-cell, or CAAR-T therapies, for autoimmune diseases. 5AM Ventures led the funding round, with participation from founding investors Adage Capital Management and the University of Pennsylvania, which also has equity in the company. Penn played a leading role in the development of the first CAR-T to reach the market, Novartis’ Kymriah (tisagenlecleucel), which the Food and Drug Administration approved for pediatric acute lymphoblastic leukemia last August.

CAAR-T cells differ from CAR-T – chimeric antigen receptor T cells – in that instead of the engineered T cells having antibody fragments, they carry the antigens that are targeted by the B cells that cause autoimmune diseases, co-founder and CEO Dr. Steven Nichtberger said in a phone interview.

“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.

Nichtberger and the other founders – Drs. Michael Milone and Aimee Payne – started the company based on research they had conducted at the university, where they are still employed.

The company’s initial focus will be mucosal pemphigus vulgaris, or mPV, an autoimmune disorder that orphan disease information website Orphanet estimates to affect one-in-2,630 people. The company’s lead product is designed to selectively eradicate B cells that produce autoantibodies to a target called desmoglein 3, or DSG3, thereby causing mPV. Nichtberger said the company would file an Investigational New Drug application to start clinical development of the CAAR-T therapy in the second half of 2019.

On the one hand, Cabaletta’s CAAR-Ts differ from CAR-Ts like Kymriah in their disease target and how they target disease-causing B cells. Yet, they are similar in the sense that they use a costimulatory domain called 4-1BB to enhance production of cytokines and a CD3-zeta signaling domain to mediate downstream signaling during T-cell activation.

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. “I can’t tell you what the risk will be, and we’ll run the trial and see,” he said.

In addition to Kymriah, the FDA last year approved another CD19-targeting CAR-T, Gilead Sciences subsidiary Kite Pharma’s Yescarta (axicabtagene ciloleucel), for adult DLBCL, and both products shared this year’s award for Best Biotechnology Product at the Prix Galien Awards. Another anti-CD19 CAR-T, Celgene subsidiary Juno Therapeutics’ JCAR017 (lisocabtagene maraleucel) is also in development, while Celgene partner bluebird bio plans to file for FDA approval of its BCMA-targeting CAR-T, bb2121, in multiple myeloma next year.

Photo: CGToolbox, Getty Images



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