CD38 is a crucial NADase in mammalian tissues that degrades NAD⁺ and thus regulates cellular NAD⁺ levels. Abnormal CD38 expression is linked to mitochondrial dysfunction under several pathological conditions. We present a novel CD38 inhibitor, compound 1, with high potency for CD38 (IC₅₀ of 11 nM) and minimal activity against other targets. In a Pus1 knockout (Pus1^-/-) mouse model of mitochondrial myopathy, compound 1 treatment rescued the decline in running endurance in a dose-dependent manner, associated with an elevated NAD⁺ level in muscle tissue, increased expression of Nrf2, which is known to promote mitochondrial biogenesis, and reduced lactate production. RNA sequencing data indicated that compound 1 has a great effect on mitochondrial function, metabolic processes, muscle contraction/development, and actin filament organization via regulating the expression of relevant genes. Compound 1 is a promising candidate for its excellent in vivo efficacy, favorable pharmacokinetics, and attractive safety profile.

2023-01-01·International Journal of Medical Sciences

Mechanism of CD38 via NAD⁺ in the Development of Non-alcoholic Fatty Liver Disease

Review

作者: Wang, Shuo ; Pei, Zuowei ; Dong, Min

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, and it can proceed to cirrhosis and hepatocellular carcinoma, as well as cardiovascular disease, chronic renal disease, and other complications, resulting in a massive economic burden. At the moment, nicotinamide adenine dinucleotide (NAD⁺) is thought to be a possible treatment target for NAFLD, besides Cluster of differentiation 38(CD38) is the primary NAD⁺ degrading enzyme in mammals and may play a role in the pathophysiology of NAFLD. For example, CD38 regulates Sirtuin 1 activity and hence affects inflammatory responses. CD38 inhibitors enhance glucose intolerance and insulin resistance in mice and lipid accumulation in the liver is greatly decreased in CD38-deficient mice. This review describes the role of CD38 in the development of NAFLD in terms of Macrophage-1, insulin resistance, and abnormal lipid accumulation in order to offer recommendations for future NAFLD pharmacological trials.

2022-12-31·mAbs

TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity

Article

作者: van Schooten, Wim ; Buelow, Benjamin ; Allison, James ; Ugamraj, Harshad S. ; Schellenberger, Ute ; Buelow, Roland ; Musnier, Astrid ; Clarke, Starlynn C ; Bijpuria, Shipra ; Poupon, Anne ; Dalvi, Pranjali ; Ouisse, Laure-Hélène ; Chini, Eduardo N. ; Iyer, Suhasini ; Manika, Sankar N. ; Dang, Kevin ; Davison, Laura M. ; Cuturi, Maria Cristina ; Castello, Giulia ; Deng, Rong

Cluster of differentiation 38 (CD38) is an ecto-enzyme expressed primarily on immune cells that metabolize nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose or cyclic ADP-ribose and nicotinamide. Other substrates of CD38 include nicotinamide adenine dinucleotide phosphate and nicotinamide mononucleotide, a critical NAD+ precursor in the salvage pathway. NAD+ is an important coenzyme involved in several metabolic pathways and is a required cofactor for the function of sirtuins (SIRTs) and poly (adenosine diphosphate-ribose) polymerases. Declines in NAD+ levels are associated with metabolic and inflammatory diseases, aging, and neurodegenerative disorders. To inhibit CD38 enzyme activity and boost NAD+ levels, we developed TNB-738, an anti-CD38 biparatopic antibody that pairs two non-competing heavy chain-only antibodies in a bispecific format. By simultaneously binding two distinct epitopes on CD38, TNB-738 potently inhibited its enzymatic activity, which in turn boosted intracellular NAD+ levels and SIRT activities. Due to its silenced IgG4 Fc, TNB-738 did not deplete CD38-expressing cells, in contrast to the clinically available anti-CD38 antibodies, daratumumab, and isatuximab. TNB-738 offers numerous advantages compared to other NAD-boosting therapeutics, including small molecules, and supplements, due to its long half-life, specificity, safety profile, and activity. Overall, TNB-738 represents a novel treatment with broad therapeutic potential for metabolic and inflammatory diseases associated with NAD+ deficiencies.Abbreviations: 7-AAD: 7-aminoactinomycin D; ADCC: antibody dependent cell-mediated cytotoxicity; ADCP: antibody dependent cell-mediated phagocytosis; ADPR: adenosine diphosphate ribose; APC: allophycocyanin; cADPR: cyclic ADP-ribose; cDNA: complementary DNA; BSA: bovine serum albumin; CD38: cluster of differentiation 38; CDC: complement dependent cytotoxicity; CFA: Freund's complete adjuvant; CHO: Chinese hamster ovary; CCP4: collaborative computational project, number 4; COOT: crystallographic object-oriented toolkit; DAPI: 4',6-diamidino-2-phenylindole; DNA: deoxyribonucleic acid; DSC: differential scanning calorimetry; 3D: three dimensional; εNAD+: nicotinamide 1,N₆-ethenoadenine dinucleotide; ECD: extracellular domain; EGF: epidermal growth factor; FACS: fluorescence activated cell sorting; FcγR: Fc gamma receptors; FITC: fluorescein isothiocyanate; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; IgG: immunoglobulin; IFA: incomplete Freund's adjuvant; IFNγ: Interferon gamma; KB: kinetic buffer; kDa: kilodalton; KEGG: kyoto encyclopedia of genes and genomes; LDH: lactate dehydrogenase; M: molar; mM: millimolar; MFI: mean fluorescent intensity; NA: nicotinic acid; NAD: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; NAM: nicotinamide; NGS: next-generation sequencing; NHS/EDC: N-Hydroxysuccinimide/ ethyl (dimethylamino propyl) carbodiimide; Ni-NTA: nickel-nitrilotriacetic acid; nL: nanoliter; NK: natural killer; NMN: nicotinamide mononucleotide; OD: optical density; PARP: poly (adenosine diphosphate-ribose) polymerase; PBS: phosphate-buffered saline; PBMC: peripheral blood mononuclear cell; PDB: protein data bank; PE: phycoerythrin; PISA: protein interfaces, surfaces, and assemblies: PK: pharmacokinetics; mol: picomolar; RNA: ribonucleic acid; RLU: relative luminescence units; rpm: rotations per minute; RU: resonance unit; SEC: size exclusion chromatography; SEM: standard error of the mean; SIRT: sirtuins; SPR: surface plasmon resonance; µg: microgram; µM: micromolar; µL: microliter.

项与 TNB-738 相关的新闻（医药）

2022-07-07

·BioSpace

The Platform that Keeps on Giving: the AstraZeneca/TeneoTwo Deal

Courtesy of Ancora Biotech The father-son team behind Teneobio and Ancora Biotech believes in its bispecific and multispecific antibody technology platform, and based on the past two years, it has every reason to do so. The impetus for Teneobio and its several spinoffs, dubbed “Teneo babies,” is a proprietary technology called UniRat. In an interview with BioSpace, Roland Buelow, Ancora’s CEO and the father half of the outfit explained the value of this platform. “With the domain antibodies you can get out of UniRat, you can make really nice bispecific or even trivalent antibody molecules,” he said. “We combined this genetically engineered animal, which is another sequence-based way to discover antibodies, and that resulted in a very large number of lead compounds that then enabled us to build multivalent antibody molecules like nobody else.” Over six years, Teneobio took five of these molecules into Phase I. Last June, Teneobio rehomed its first “Teneo baby”, TeneoOne, and the multiple myeloma asset it represented, to AbbVie, with whom it originally partnered in 2019. Just one month later, Amgen snapped up the rest of the company, along with its CD3 engager technology, in a deal that could yield $2.5 billion. With three high-potential molecules left behind, Roland and his son, Ben Buelow, spun out Ancora to continue capitalizing on the platform. Lightspeed Venture Partners, along with SR One, provided Series A funding for the company in June. Not a month later, AstraZeneca came calling for TNB-486 (TeneoTwo), which it acquired for $100 million upfront in a deal announced Tuesday. Ancora stands to receive another $1.165 billion in R&D milestones and commercial-related payments. AstraZeneca Claims Remaining CD3 Engager Asset TNB-486 belongs to a class of therapeutic antibodies called T cell engagers. It is the only molecule created with the CD3 engager technology that did not go with Amgen. The drug, which is in Phase I development for relapsed and refractory B-cell non-Hodgkin lymphoma, can activate and recruit T cells to trigger an immune response. “These are proteins that replicate the way CAR T cells work in the body,” Ben Buelow, Ancora’s CMO, explained. “So, one arm will bind to the T cell that's already in the person's body. The other side binds to whatever you're targeting, usually tumor cells, and then that interaction essentially forces that T cell to kill whatever it's bound to.” While CD19 has been targeted extensively by CAR T cell therapies in lymphoma, “all of those molecules have been associated with fairly significant toxicity and as a result, the second generation T cell engager molecules were mostly aimed at CD20,” Buelow said. He added that there are a number of molecular advantages to targeting CD19. “With our unique anti-CD3, which is really good still at getting T cells to kill the target but tends to induce less of the molecules released by T cells that cause the side effects, we thought we could kind of revive this target.” He shared that the clinical data, which Ancora expects to be published within the next six to 12 months, “essentially bears that out.” Of Ancora’s newest collaborator, Buelow said, “AstraZeneca is a very science-savvy company for a large pharma partner, and they recognized those unique qualities.” While there is a sentiment in the industry that CAR T therapies will run the table in any space they play, “We believe that bispecific T cell engagers have many advantages and that there's plenty of space for both types of technology,” he said, “I think [AstraZeneca] recognized that as well.” On the AstraZeneca side, Anas Younes, senior vice president of Hematology R&D stated, “We believe this innovative molecule, which was designed to optimize the therapeutic window of T cell activation, will enable us to explore novel combinations that have the potential to become new standards of care in this setting.” Galym Imanbayev, a partner at Lightspeed Venture Partners who was instrumental in leading the firm’s investment in Ancora, shared his perspective on AstraZeneca’s motives. “To a large extent it fits a need in the pipeline, and to be relevant in a modality that they haven't had as much as their competitors,” he told BioSpace. Driving the Future for Ancora The revenues from the AbbVie, Amgen and now AstraZeneca deals have set Ancora up for success with its two remaining assets. “It's rare that you have a biotech company that has two clinical-stage assets before it ever gets Series B fundraising,” Ben Buelow said. “All of that science work, all of the manufacturing, all of the IND, was essentially bought and paid for before the company was even started and that gave us an incredible advantage.” The deal with AstraZeneca “gave us the resources and the runway to essentially realize the full potential of the molecules we have coming after, and to buy ourselves the time we need to convince the world that they are as good as we know that they are,” he shared. Ancora’s two outstanding assets target inflammatory and fibrotic diseases. While the drugs, TNB-738 and an anti-HBVxCD3 molecule, are rumored to exist in the anti-aging space, Buelow said the true focus is more complex. “There is an emerging body of literature that essentially shows that there may be common themes in terms of the biology that underpins susceptibility to certain classes of diseases. As a group, those are sometimes quaintly referred to as ‘inflammaging’ type diseases, but they in fact incorporate many very discrete entities,” he explained. A few examples include post-viral lung fibrosis (pulmonary fibrosis), ischemia-reperfusion injury, inflammatory bowel disease and metabolic syndrome. Ancora’s current emphasis is on TNB-738, or TeneoFour, a CD38 enzyme inhibitor designed to reduce inflammation in fibrosis. Both a bivalent and a biparatopic, it can bind to different parts of the same molecule. “We have very carefully and very effectively defined the underlying cellular molecular biology, but I think on a clinical level it's just a very large landscape of potential,” Buelow shared. Will TNB-738 also be sold to a company beginning with the letter "A"? Only time will tell. An Effective Model for Today? In the current biotech landscape, where venture capital funding could be tough to come by for the foreseeable future, Teneobio/Ancora’s business model looks particularly savvy. “I think we're so used to, particularly on the tech investor side, platforms, platforms, platforms, and then everyone thinks that you sell a platform and everything goes along with it,” Imanbayev said. “By breaking things up, you immediately set the heuristic of the acquirer in a different mindset. You not only get the benefit of avoiding that diversification discount, but you also get the benefit of time.” This model, he pointed out, has led to an ascension of appreciation with each deal the Buelows have struck. “I think there's an interesting element here that not only we as investors can learn from, but other biotech companies as well.”

抗体细胞疗法合作

2022-06-12

·PRNewswire

Gracell Biotechnologies Presents Updated Clinical Data for BCMA/CD19 Dual-targeting FasTCAR GC012F in RRMM at EHA2022 Congress, Highlighting 100% MRD Negativity Rate in All Treated Patients

Gracell also presented data on GC012F for treatment of B-NHL and allogeneic TruUCAR-candidate GC502 for treatment of B-ALL Management to host clinical update call on Monday, June 13, at 8:00AM ET SAN DIEGO, Calif. and SUZHOU and SHANGHAI, China, June 12, 2022 /PRNewswire/ -- Gracell Biotechnologies Inc. ("Gracell" or the "Company",NASDAQ: GRCL), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, today announced the updated clinical data from a multicenter study evaluating GC012F, the Company's autologous CAR-T therapeutic candidate dual-targeting B-cell maturation antigen (BCMA) and CD19, for the treatment of relapsed/refractory multiple myeloma (RRMM). Gracell shared the data at the European Hematology Association 2022 Hybrid Congress (EHA2022 Congress), held from June 9-12 in Vienna, Austria. "The updated data of the final dataset of 29 treated patients underscore the deep responses achieved with GC012F, including a 100% MRD negativity rate in all patients treated," commented Dr. Martina Sersch, Chief Medical Officer of Gracell. "GC012F for the treatment of RRMM continues to demonstrate a favorable safety profile and a promising mDOR of 15.7 months in mostly high risk, heavily pretreated patients, including those with extramedullary disease and those who were previously exposed to PI, IMiDs and anti-CD38 agents. In addition, we presented at EHA the first-in-human data of GC012F in B-NHL, a potential second indication. We look forward to continuing developing this lead asset and providing a new treatment option to the patients with high unmet needs." Additionally, on June 10, Gracell presented the first clinical results of the first-in-human phase 1 investigator-initiated study (IIT) in China evaluating the safety and tolerability of GC012F in B-cell non-Hodgkin's lymphoma patients, and longer-term follow-up results of a safety and efficacy study from an IIT evaluating allogeneic TruUCAR-T GC502 in patients with B-cell acute lymphoblastic leukemia. Gracell announced these data in a press release on May 12. BCMA/CD19 Dual-Targeting FasTCAR-T GC012F for the Treatment of RRMM From October 2019 to January 2022, 29 heavily pretreated RRMM patients were enrolled and treated in this single-arm, open label, multicenter IIT with a single infusion of GC012F at three dose levels: 1x105 cells/kg (DL1), 2x105 cells/kg (DL2), and 3x105 cells/kg (DL3). 90% (26/29) patients were high risk based on mSMART 3.0 criteria and patients had received a median of five prior lines of therapy. At the data cutoff of June 8, 2022, the 29 patients had been evaluated for response with a median follow-up duration of 11 months, ranging from 4.9 to 34.5 months. Patients continue to be followed for deepening responses. The response rate at different dose levels was 100% (2/2) in DL1, 80% (8/10) in DL2, and 100% (17/17) in DL3. All patients 100% (29/29) achieved minimal residual disease (MRD) negativity. 75.9% (22/29) of all patients treated achieved MRD- sCR. Median duration of response (DOR) at data cut off was 15.7 months (95% CI: 7.6-33.1). The safety profile of GC012F was consistent with previous findings with mostly low grade of cytokine release syndrome (CRS). 93% (27/29) of events were Grade 0-2 and 7% (2/29) of events were Grade 3. No Grade 4 or 5 CRS, or any Grade immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Patients continue to be monitored for safety and efficacy including best overall response (BOR) and DOR. Due to the COVID-19 related lockdowns at the lead site of the study in Shanghai, China, follow-up assessment visits of certain patients were delayed and Gracell is looking forward to providing further updates in future publications for DOR, ORR, and BOR in all treated patients. In November 2021, GC012F was granted Orphan Drug Designation for the treatment of multiple myeloma by the U.S. Food and Drug Administration. Details of the presentation are as follows: Abstract title: Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting FasTCAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM) Session title: Relapsed/refractory myeloma: BCMA-directed therapies Presentation time: Sunday, June 12 from 11:30 AM – 12:45 PM CEST Presentation location: Hall A2-A3 For more information about the EHA2022 Hybrid Congress, visit . Clinical update conference call and webcast details Monday, June 13, 2022 @ 8:00AM ET Investor domestic dial-in: (833) 693-0545 Investor international dial-in: +1(661) 407-1586 Conference ID: 1820109 Live webcast link: A replay of the webcast will be available on ir.gracellbio.com shortly after the conclusion of the event for 90 days. About GC012F GC012F is a FasTCAR-enabled dual-targeting CAR-T product candidate that is currently being evaluated in IIT studies in China for the treatment of multiple myeloma and B-cell non-Hodgkin's lymphoma. GC012F simultaneously targets CD19 and BCMA to drive fast, deep and durable responses, which can potentially improve efficacy and reduce relapse in multiple myeloma and B-NHL patients. About FasTCAR CAR-T cells manufactured on Gracell's proprietary FasTCAR platform appear younger, less exhausted and show enhanced proliferation, persistence, bone marrow migration and tumor cell clearance activities as demonstrated in preclinical studies. With next-day manufacturing, FasTCAR is able to significantly improve cell production efficiency which may result in meaningful cost savings, and, together with fast release time, enables enhanced accessibility of cell therapies for cancer patients. About Gracell Gracell Biotechnologies Inc. ("Gracell") is a global clinical-stage biopharmaceutical company dedicated to discovering and developing breakthrough cell therapies. Leveraging its pioneering FasTCAR and TruUCAR technology platforms and SMART CARTM technology module, Gracell is developing a rich clinical-stage pipeline of multiple autologous and allogeneic product candidates with the potential to overcome major industry challenges that persist with conventional CAR-T therapies, including lengthy manufacturing time, suboptimal cell quality, high therapy cost and lack of effective CAR-T therapies for solid tumors. For more information on Gracell, please visit . Follow @GracellBio on LinkedIn. Cautionary Noted Regarding Forward-Looking Statements Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to the expected trading commencement and closing date of the offering. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including factors discussed in the section entitled "Risk Factors" in Gracell's most recent annual report on Form 20-F as well as discussions of potential risks, uncertainties, and other important factors in Gracell's subsequent filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Gracell specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. Readers should not rely upon the information on this page as current or accurate after its publication date. Media contacts Marvin Tang [email protected] Kyle Evans [email protected] Investor contacts Gracie Tong [email protected] Stephanie Carrington [email protected] SOURCE Gracell Biotechnologies Inc.

孤儿药细胞疗法

2022-06-09

·Endpoints

Exclusive: After Amgen exit, father-son duo gets Lightspeed backing to fund remaining Teneobio 'babies'

The father-son duo behind Teneobio is back with another biotech, comprising three bispecific antibodies that neither Amgen wanted when dishing out $900 million upfront last year, nor AbbVie wanted when acquiring a multiple myeloma asset in 2019. Technically, Ancora Biotech is three shell companies, one for each of its antibodies or “Teneo babies,” CEO Roland Buelow told Endpoints News . The “unconventional” route is meant to give each asset optionality on its path to market, just like the path set by Teneobio, said CMO Ben Buelow, Roland’s son. “We are in a position eventually to take these companies either public and get them funded for registrational trials and eventual approval, or we have the possibility to sell them off like we have done so far,” the CEO said. The 10-person startup is getting $60 million in backing from Lightspeed Venture Partners — one of the original Teneobio investors — and SR One. Buelow fueled Ancora with $10 million when it first kicked into gear after last year’s Amgen exit, he said. “When I tell people about the story of Teneobio, I always talk about the movie ‘The Blues Brothers,’ getting the band back together, because Roland pulled all of the best people he’d worked with over his 25-30 years of biotech experience into that company,” the younger Buelow said. Other Teneobio execs have gone on to launch biotechs, including Rondo Therapeutics. The elder Buelow has a history of constructing biotechs and selling them off. Prior to Teneobio, he built up human antibody developer Open Monoclonal Technology, which sold to Ligand Pharmaceuticals for $178 million in 2015. It’s now going public via a SPAC spinoff at an $850 million valuation. Back to Ancora: Two of the biotech’s “babies” are already in the clinic. A dose-escalation study is underway for CD19- and CD3-targeting TNB-486, which is anticipated to be a lymphoma treatment, the CEO said. Close to 30 patients have been enrolled and the first round of data will come out at ASH this year or the annual ASCO conference next year, the CMO said, noting the company is close to choosing the recommended Phase II dose. Right now, TNB-486 is in the third-line-plus setting, but Ancora hopes to move into earlier lines by combining it with other therapies, the CMO noted. About 80 patients are expected to enroll in the early-stage study being conducted in the US and Korea, according to the clinical trials register. Ancora’s second clinical-stage asset, TNB-738, is a CD38 enzyme inhibitor designed to tamp down inflammation in fibrosis and treating age-related diseases, the CEO said. Ben Buelow said the drug is in a Phase I healthy volunteer study. The Australia-based trial aims to enroll 64 patients and collect the last primary outcome data in December, according to the clinical trials database. “It’s a really novel mechanism and oftentimes, when you have something like that, we believe in that molecule in a very substantial way and until other people see the light on that, we may have to take it for quite a ways ourselves,” the medical chief explained. A “basket-like approach” is anticipated for the bispecific, the CMO said, as multiple Phase Ib/II studies will consider various “clinical indications of interest.” At the bottom of the pipeline is a preclinical anti-HBsAg x CD3 antibody being considered for chronic hepatitis B infections. Expect a 2024 human trial entry, Lightspeed said. With just 10 employees, half on the clinical development team, Ancora is steering the ship with a lean crew. It will stay that way. “We are planning to continue to run these studies as much as possible remotely, virtually, to keep costs down,” the CMO said, “so currently there is no plan to increase our team size.” Ancora derives its name from the Italian word for anchor and again. An anchor resembles the shape of an antibody, the CMO said, so the company “thought that was cute” when coming up with the brand. The startup isn’t to be confused with Ancora Bio , the fifth biotech to come out of ex-Novartis CEO Joe Jimenez’s Aditum incubator, which is testing a failed Taisho depression drug.

抗体ASCO会议

100 项与 TNB-738 相关的药物交易

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研发状态

适应症	最高研发状态	国家/地区	公司
纤维化	临床前	美国更多	TeneoFour 更多
炎症	临床前	美国更多	Ancora Innovation LLC初创企业更多
代谢性疾病	临床前	美国更多	TeneoFour 更多