MAP3K12

WALTHAM, Mass.--(BUSINESS WIRE)-- Minerva Biotechnologies Corporation, a private company developing 1st-in-human therapies for the treatment of solid tumor cancers, announced today that the FDA has approved their IND (Investigational New Drug) application to conduct clinical trials with huMNC2-CAR22, aka MUC1*-CAR-1XX, for the treatment of metastatic breast cancers. huMNC2-CAR22 targets MUC1* (muk 1 star), the growth factor receptor that drives the growth and metastasis of most solid tumor cancers. Minerva’s first CAR T that targets MUC1*, huMNC2-CAR44, is already in a clinical trial for metastatic breast cancers. Initial results show CAR T cell expansion, patients going from Progressive Disease to Stable Disease and Partial Response. However, for a durable response, we needed to overcome CAR T cell exhaustion, which is common to CAR T cell treatment of solid tumor cancers. This second MUC1* CAR T, huMNC2-CAR22, bears the “1XX” mutations in the T cell’s CD3-z signaling domain. These four Tyrosine to Phenylalanine mutations block tyrosine phosphorylation in two of the three signaling domains of CD3-z, which slow signaling and dramatically increase persistence. Unexpectedly, the 1XX mutations give the CAR T cells the added benefit of being able to recognize and kill the low antigen expressing cancer cells that lead to cancer recurrence. “These 1XX mutations solve the two hurdles that have thus far stood in the way of an effective CAR T treatment for solid tumor cancers: 1) CAR T cell exhaustion; and 2) failure to kill the low antigen expressing cells,” said Minerva’s CEO Dr. Cynthia Bamdad, “Together with our MUC1* antibodies that recognize an epitope only available on cancer cells, huMNC2-CAR22 promises to be a big leap ahead in our fight against cancers.” We thank our scientists, collaborators, and the patients and their families for their courage. Minerva holds a license from Memorial Sloan Kettering for use of the 1XX technology. About the trial NCT04020575 is a first-in-human trial of huMNC2-CAR22 and huMNC2-CAR44, autologous CAR T cells targeting MUC1* in metastatic breast cancer in patients with MUC1* positive tumors.

Scientists have identified a new role for a protein complex at the center of a human genetic disorder called Bardet-Biedl syndrome, or BBS, for which there is currently no cure. Bardet-Biedl syndrome arises when the BBSome protein complex malfunctions. Because the BBSome regulates the form and function of cilia, the hair-like structures on the surface of cells, BBS has been classified as a disease of the cilia. But the wide spectrum of symptoms associated with BBS -- the most common of which is vision loss, as well as obesity, extra fingers or toes and kidney malfunction -- have led to hypotheses that the cause of the syndrome may not lie solely within the cilia. In a new study published in Developmental Cell, a team from the University of Michigan Life Sciences Institute now offers the first known direct evidence for these hypotheses. Their findings demonstrate that the BBSome operates outside of cilia to support sight, at least in one common model species. The discovery began when scientists in the lab of LSI faculty member Shawn Xu were investigating how tiny roundworms called Caenorhabditis elegans can sense light despite having no eye-like organs. Because C. elegans have a simple and well-mapped nervous system, the Xu lab uses them as a model to understand the fundamental biology behind various forms of sensation. The team performed a genetic screen, a process of introducing random mutations to identify which genes are required for a given biological process, to find the genes involved in the worms' ability to respond to light. Most of the mutations that caused worms to stop sensing light turned out to be in the BBSome. And, like the progressive vision loss that BBS patients experience, the worms with BBSome mutations progressively lost the ability to sense light as they aged. advertisement Through a series of several more experiments, the team discovered that the BBSome plays a role in light sensation independent of its role in the cilia. In one scenario, they mutated C. elegans to remove all cilia; in a second experiment, they left the cilia on the worms but prevented the BBSome from getting to the cilia. In both cases, the worms were still able to sense light, so long as the BBSome functioned in the rest of the cell. "It's a great demonstration of the power of model organisms," said Xinxing Zhang, a postdoctoral researcher in the Xu lab and the study's lead author. "Cilia are essential for most organisms. But we can remove cilia from the C. elegans and they still survive, allowing us to uncover this unexpected role for the BBSome completely independent of the cilia." Xu's lab previously discovered that C. elegans sense light through a receptor protein called LITE-1 that sits at the surface of neurons and sends signals to the central nervous system to respond to the light (in the worms' case, by moving away from it). In this latest study, the team found that when BBSome malfunctions within the cell, LITE-1 receptors are pulled back into the cell from the surface and then broken down, preventing the worms from sensing light. In a second genetic screen, the scientists discovered that the process of degrading LITE-1 is controlled through another protein called DLK. The BBSome prevents DLK from starting a chain reaction that inappropriately breaks down LITE-1. Both BBSome and DLK are conserved in humans, and the researchers were able to show that BBSome similarly blocks DLK expression in human cells. They believe that this BBSome-DLK-photosensor pathway could be involved in the vision loss that is so prominent in patients with Bardet-Biedl Syndrome. "Because BBS is known to be caused by defects in the BBSome, there has been a longstanding assumption that the disorder must be tied to the cilia," said Xu, who is also a professor of molecular and integrative physiology in the U-M Medical School. "We are not disputing that BBS is tied to defects in the cilia. We are just offering direct evidence that the BBSome can also function outside of cilia, and it has a role there related to light sensation. Perhaps this can broaden the view of how to develop treatments for BBS." This research was supported by the National Institutes of Health.

Minerva Biotechnologies Corporation announced today that its trial of huMNC2-CAR44 T cells (NCT04020575) has now opened at City of Hope, Duarte, California. This is a first-in-human trial targeting the tumor-associated form of MUC1, called MUC1* (muk 1 star). MUC1* is the transmembrane cleavage product that is a growth factor receptor that drives growth of an estimated 93% of breast cancers. The antibody that targets Minerva’s CAR T to the tumor binds to an ectopic site that is only exposed after cleavage and release of the tandem repeat domain. Other attempts at targeting MUC1 with antibodies, ADCs, or CAR Ts have targeted the tandem repeat domain, which is cleaved in the tumor microenvironment and shed from the cell surface. The huMNC2-CAR44 therapy was developed by, and is proprietary to, Minerva Biotechnologies. The targeting head of the CAR, the antibody MNC2, recognizes a unique conformation of MUC1 after cleavage by a specific enzyme in the tumor microenvironment. “The ability of our antibody to bind specifically to the cancerous form of MUC1 without binding to MUC1 on normal tissues is a real breakthrough,” said Dr. Cynthia Bamdad, CEO of Minerva Biotechnologies. “Demonstration of safety and early signs of efficacy of huMNC2-CAR44 represent a significant milestone for Minerva. We have a broad, deep pipeline that includes next generation CAR Ts, with enhanced in vivo persistence, and the ability to target cells with much lower antigen density, allowing us to challenge the persistence issues seen elsewhere in the field. We can now progress these to the clinic with increased confidence. We are also developing therapeutics that target the onco-embryonic growth factor, NME7, that activates the MUC1* growth factor receptor across many different types of solid tumors and the preclinical results are very encouraging,” said Minerva Chief Business Officer, Michael Crowther. We would like to express our gratitude to our collaborators, our scientists, and the patients and their physicians for their support and participation in this trial. About the trial NCT04020575 is a first-in-human trial of huMNC2-CAR44, an autologous CAR T therapy targeting MUC1* in metastatic breast cancer in patients with MUC1* reactive tumors.