Author: Clark, Michael R ; Kirton, Christopher M ; Ellison, Cara J ; Smith, Cheryl S ; Wilkes, Anthony M ; Armour, Kathryn L ; Williamson, Lorna M ; Ip, Natasha C Y

We previously produced a recombinant version of the human anti-RhD antibody Fog-1 in the rat myeloma cell line, YB2/0. When human, autologous RhD-positive red blood cells (RBC) were sensitised with this IgG1 antibody and re-injected, they were cleared much more rapidly from the circulation than had been seen earlier with the original human-mouse heterohybridoma-produced Fog-1. Since the IgG have the same amino acid sequence, this disparity is likely to be due to alternative glycosylation that results from the rat and mouse cell lines. By comparing the in vitro properties of YB2/0-produced Fog-1 IgG1 and the same antibody produced in the mouse myeloma cell line NS0, we now have a unique opportunity to pinpoint the cause of the difference in ability to clear RBC in vivo. Using transfected cell lines that express single human FcγR, we showed that IgG1 made in YB2/0 and NS0 cell lines bound equally well to receptors of the FcγRI and FcγRII classes but that the YB2/0 antibody was superior in FcγRIII binding. When measuring complexed IgG binding, the difference was 45-fold for FcγRIIIa 158F, 20-fold for FcγRIIIa 158V and approximately 40-fold for FcγRIIIb. The dissimilarity was greater at 100-fold in monomeric IgG binding assays with FcγRIIIa. When used to sensitise RBC, the YB2/0 IgG1 generated 100-fold greater human NK cell antibody-dependent cell-mediated cytotoxicity and had a 103-fold advantage over the NS0 antibody in activating NK cells, as detected by CD54 levels. In assays of monocyte activation and macrophage adherence/phagocytosis, where FcγRI plays major roles, RBC sensitised with the two antibodies produced much more similar results. Thus, the alternative glycosylation profiles of the Fog-1 antibodies affect only FcγRIII binding and FcγRIII-mediated functions. Relating this to the in vivo studies confirms the importance of FcγRIII in RBC clearance.

News (Medical) associated with FOG-001

28 Oct 2024

·endpts.com

FogPharma rebrands as Parabilis Medicines, as CEO Mathai Mammen highlights next drugs

FogPharma is renaming itself as Parabilis Medicines, announcing a new corporate identity Monday that reflects the imprint left by CEO Mathai Mammen since joining in 2023. The name change is the highest-profile sign of Mammen’s tenure, but the former Johnson & Johnson R&D head has also reshaped its workforce, its next cancer programs and the focus of its platform. In an exclusive interview with Endpoints News , Mammen said the rebrand acknowledges that the startup is “a very different-looking company than we were 16 months ago” when he started. Founded in 2016 by biotech entrepreneur Greg Verdine , Fog is an acronym for “Friends of Greg” referencing the high-net-worth individuals who backed its seed round. Part of the reason for the new name, Mammen said, is Fog couldn’t be trademarked and would sometimes get confused with similarly named Foghorn Therapeutics. Verdine left the board in June, after serving as vice chair for a year to help with the transition. The Cambridge, MA-based biotech is developing helix-shaped peptide drugs to slip inside cells with more binding power than small molecules. Its lead program, FOG-001, entered the clinic last June, and Mammen said they expect an initial data readout at a medical conference in the first half of 2025. FOG-001 targets beta-catenin, a hard-to-drug protein that drives many cancer cases, particularly in colorectal, prostate, and melanoma. An ongoing Phase 1/2 study is primarily enrolling late-stage colorectal cancer patients who don’t have other treatment options. Mammen called emerging clinical data “really encouraging,” as he expects to finish dose escalation in the coming months. “I’ve seen a lot of drug programs,” Mammen said, citing his J&J experience. “I feel like I have an eye for what might work, and this one feels very much like a drug to me.” Mammen said the company is considering potential pharma partnerships, particularly on FOG-001, which he called “a very complicated program” given the range of cancer types and potential combination therapies that could be tested. While FOG-001 was headed into the clinic before Mammen arrived, he has been hands-on in selecting Parabilis’ next programs. He’s prioritized its efforts in protein degradation, seeing its peptide approach as well-suited to tackling proteins that small-molecule degraders can’t hit. He highlighted four preclinical programs to watch beyond FOG-001, three of which are respectively degraders of beta-catenin, ERG, and AR. The fourth program is a radioligand therapy in collaboration with Artbio. Parabilis could soon be selecting development candidates for all of these programs, Mammen said, with the ERG degrader expected to reach that milestone in the next quarter or two. The broad goal is to begin filing INDs for these programs at the end of 2025 and into 2026, he added. “We’re really excited about these four as diversifying well beyond ‘001,” he said. With its $145 million Series E round announced earlier this year , Parabilis has a cash runway into 2026, Mammen said. The company has raised just over $500 million since its founding.

Executive Change

01 Mar 2024

·medcitynews.com

Cancer Biotech Lands $145M for First-in-Class Drug to Block Elusive Tumor Target

FogPharma’s has reached early clinical development with therapeutic candidate that takes a novel approach to treatment solid tumors. The company now has $145 million to continue the drug’s clinical development and advance more programs in its pipeline. The drugs of Cambridge, Massachusetts-based FogPharma discovers and develops peptides capable of entering cells to address targets that drive disease. Such targets haven’t been drugged before due to the difficulty of getting a drug to act within a cell. FogPharma says its peptide drugs, which it calls Helicon therapeutics, can get inside a cell to modulate protein-protein interactions as well as protein-DNA interactions. FogPharma’s lead program is FOG-001, a Helicon therapeutic designed to block a key step I the Wnt/beta-catenin signaling pathway. Hyperactivation of this pathway is associated with the development and progression of various types of cancer, including colorectal, hepatocellular, and endometrial tumors. While this pathway has validation for playing a role in cancer, its location inside a cell has made it inaccessible to drugs that are antibodies or small molecules. FOG-001 is administered as a once-weekly infusion. A Phase 1/2 clinical trial is evaluating the drug in patients with locally advanced or metastatic solid tumors, including colorectal cancer. The first patient was dosed last June. The trial’s targeted enrollment is about 200 participants. “We believe FOG-001 may represent the long-awaited major technological breakthrough needed to address one of the most common yet unaddressed oncogenic signaling pathways,” FogPharma Chairman, President, and CEO Mathai Mammen said in a prepared statement. “This financing will allow us to execute on our expanded clinical development and commercialization strategy to deliver FOG-001 to patients, while simultaneously strengthening our discovery efforts against other compelling intracellular targets that drive a range of diseases.” The FogPharma pipeline also includes discovery-stage program in development to address targets associated with prostate cancer, ovarian cancer, lung cancer, and more. FogPharma’s last financing was a $178 million Series D financing in late 2022. The company was founded by Greg Verdine, a former Harvard chemistry professor who has become a serial biotech entrepreneur. The new financing announced Friday, a Series E round, was led by Nextech Invest. Investor and entrepreneur Alexis Borisy will join the FogPharma board in the position designated to Nextech. Other new investors that joined FogPharma’s latest financing include RA Capital Management, Rock Springs Capital, General Catalyst, Marshall Wace, Samsara Biocapital, Foresite Capital, Symbiosis, Catalio Capital Management, Sixty Degree Capital, and Johnson & Johnson’s former chairman and CEO Alex Gorsky. Image by the National Cancer Institute

Executive ChangePDC

01 Mar 2024

·www.fiercebiotech.com

FogPharma clears $145M series E thanks to Alexis Borisy, ex-J&J CEO Alex Gorsky

Even before Mathai Mammen, M.D., Ph.D., began his tenure in March 2023, FogPharma was already able to pull in massive fundraising rounds. We all aspire to have a boss who will just give you money for your next endeavor. Mathai Mammen, M.D., Ph.D., happens to have just that. Johnson & Johnson’s former pharma R&D chief, now the CEO of FogPharma, has brought on former J&J CEO Alex Gorsky as an investor in the company’s $145 million series E. Gorsky joins a syndicate of heavyweights like RA Capital and General Catalyst who became first-time Fog investors. Returning investors included Arch, GV and Fidelity. Another big name on the bill is serial biotech entrepreneur Alexis Borisy, who also joined the board on behalf of Nextech, which led the round. You don’t see too many series Es in the wild these days, but the IPO markets have been rewarding more mature clinical companies in the first months of the year. Fog, evidently, found clarity in another private round. “This financing will allow us to execute on our expanded clinical development and commercialization strategy to deliver FOG-001 to patients, while simultaneously strengthening our discovery efforts against other compelling intracellular targets that drive a range of diseases,” Mammen said. FOG-001 is an intracellular TCF-blocking β-catenin inhibitor being tested in a phase 1/2 trial for solid tumors. Mutations of the Wnt/β-catenin pathway, which the drug targets, are particularly common in colorectal cancer. “Millions of colorectal cancer patients have been told by their oncologists that no more can be done for them. We believe FOG-001 may represent the long-awaited major technological breakthrough needed to address one of the most common yet unaddressed oncogenic signaling pathways,” Mammen said. The med came off of Fog’s Helicon platform, which combines tunable stabilized helical peptides with computational physics and artificial intelligence to churn out new medicines. Further cash from the fundraising will be used to support Fog’s earlier pipeline. Even before Mammen began his tenure in March 2023, Fog has been able to pull in massive fundraising rounds. In November 2022, the company raised $178 million, which followed a $107 million series C in March 2021. Beyond FOG-001, the company lists a range of programs in preclinical development covering a variety of different cancer mutations.

IPOExecutive Change

100 Deals associated with FOG-001

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Indication	Highest Phase	Country/Location	Organization	Date
Adenomatous Polyposis Coli	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023
Atrial Premature Complexes	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023
Gastrooesophageal junction cancer	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023
Locally Advanced Malignant Solid Neoplasm	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023
metastatic non-small cell lung cancer	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023
Neoplasm Metastasis	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023
Non-small cell lung cancer stage IIIB	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023
small cell carcinoma non	Phase 2	US	Fog Pharmaceuticals, Inc.Startup	23 May 2023

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