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Celldex Therapeutics, Inc. (CLDX)

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  • l
    longvrts
    Report out: Mast cells contribute to osteoarthritis. There are currently no good treatments for OA. CDX-0159 is the first-in-class and best-in-class anti-inflammatory mast cell inhibitor. OA represents a very substantial market opportunity for 0159:

    Int J Mol Sci. 2022 Jan 4;23(1):541. doi: 10.3390/ijms23010541.

    Mast Cells Differentiated in Synovial Fluid and Resident in Osteophytes Exalt the Inflammatory Pathology of Osteoarthritis

    Priya Kulkarni 1, Abhay Harsulkar 1 2, Anne-Grete Märtson 3, Siim Suutre 4, Aare Märtson 5 6, Sulev Koks 7 8

    PMID: 35008966 PMCID: PMC8745477 DOI: 10.3390/ijms23010541
    Free PMC article
    Full text linksCite
    Abstract
    Introduction: Osteophytes are a prominent feature of osteoarthritis (OA) joints and one of the clinical hallmarks of the disease progression. Research on osteophytes is fragmentary and modes of its contribution to OA pathology are obscure.

    Aim: To elucidate the role of osteophytes in OA pathology from a perspective of molecular and cellular events.

    Methods: RNA-seq of fully grown osteophytes, collected from tibial plateau of six OA patients revealed patterns corresponding to active extracellular matrix re-modulation and prominent participation of mast cells. Presence of mast cells was further confirmed by immunohistochemistry, performed on the sections of the osteophytes using anti-tryptase alpha/beta-1 and anti-FC epsilon RI antibodies and the related key up-regulated genes were validated by qRT-PCR. To test the role of OA synovial fluid (SF) in mast cell maturation as proposed by the authors, hematopoietic stem cells (HSCs) and ThP1 cells were cultured in a media supplemented with 10% SF samples, obtained from various grades of OA patients and were monitored using specific cell surface markers by flow cytometry. Proteomics analysis of SF samples was performed to detect additional markers specific to mast cells and inflammation that drive the cell differentiation and maturation.

    Results: Transcriptomics of osteophytes revealed a significant upregulation of mast cells specific genes such as chymase 1 (CMA1; 5-fold) carboxypeptidase A3 (CPA3; 4-fold), MS4A2/FCERI (FCERI; 4.2-fold) and interleukin 1 receptor-like 1 (IL1RL1; 2.5-fold) indicating their prominent involvement. (In IHC, anti-tryptase alpha/beta-1 and anti- FC epsilon RI-stained active mast cells were seen populated in cartilage, subchondral bone, and trabecular bone.) Based on these outcomes and previous learnings, the authors claim a possibility of mast cells invasion into osteophytes is mediated by SF and present in vitro cell differentiation assay results, wherein ThP1 and HSCs showed differentiation into HLA-DR+/CD206+ and FCERI+ phenotype, respectively, after exposing them to medium containing 10% SF for 9 days. Proteomics analysis of these SF samples showed an accumulation of mast cell-specific inflammatory proteins.

    Conclusions: RNA-seq analysis followed by IHC study on osteophyte samples showed a population of mast cells resident in them and may further accentuate inflammatory pathology of OA. Besides subchondral bone, the authors propose an alternative passage of mast cells invasion in osteophytes, wherein OA SF was found to be necessary and sufficient for maturation of mast cell precursor into effector cells.

    Keywords: RNA-seq; immune cell differentiation; mast cells; osteoarthritis; osteophytes; proteomics; synovial fluid.
  • l
    longvrts
    Cowen Financial SEC 13G: declares over 5% ownership
  • l
    longvrts
    1/4/22 CDX-301 NCT03804944 trial update: clinical PII trial combining CDX-301 + Pembrolizumab + Letrozole + Radiation has successfully reached primary completion date on Dec 30 '21 as initially projected. This immunotherapy trial in breast cancer patients is a collaboration between Cornell Univ, DOD, MRK and CLDX. The trial continues to recruit patients and even opened new sites. Hard to say what it all means- in general these type of immunotherapy approaches are challenging. However, the successful primary endpoint completion and continuing recruitment overall give a positive signal:

    "Converting HR+ Breast Cancer Into an Individualized Vaccine (CBCV)

    ClinicalTrials.gov Identifier: NCT03804944
    Recruitment Status : Recruiting
    First Posted : January 15, 2019
    Last Update Posted : July 16, 2021
    See Contacts and Locations
    Sponsor:
    Weill Medical College of Cornell University
    Collaborators:
    United States Department of Defense
    Merck Sharp & Dohme Corp.
    Celldex Therapeutics
    Information provided by (Responsible Party):
    Weill Medical College of Cornell University

    Study DetailsTabular ViewNo Results PostedDisclaimerHow to Read a Study Record
    Study Description
    Go to sections
    Brief Summary:
    Newly diagnosed post-menopausal women with clinical stage II-III, HR+HER2- breast cancer are eligible to a randomized trial, concurrently open at five US academic institutions. Patients receiving 4 months of standard neoadjuvant hormonal therapy with letrozole are randomly assigned to one of 4 arms of a trial testing focal hypo-fractionated RT alone or with immunotherapy combinations.

    Condition or disease Intervention/treatment Phase
    Breast Cancer
    Radiation: Focal Radiation therapy
    Drug: Pembrolizumab (200mg IV for 30 minutes
    Biological: CDX-301
    Phase 2

    Detailed Description:
    Patients will be on the study for a total of 5 months, this includes 4 months on active study intervention, with breast surgery at week 16 and one month follow up period, after surgery. Patients will be randomly assigned to one of these 4 arms - 1. Anti-PD1 antibody pembrolizumab (Keytruda, Merck) will be infused day 12, at the standard dose of 200 mg IV over 30 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity. 2. FLT3L (CDX-301, the recombinant human protein by Celldex) will be self-administered subcutaneously, in 5 consecutive daily injections, week 1, day 1-5. 3. For all arms radiation therapy to the breast tumor will begin on week 2 (Day 8,10,12), at dose of 8 Gy x 3 fractions, every other day. 4. Letrozole (Femara ®, Novartis) 2.5 mg tabs, once a day, daily for 4 months, until surgery, and thereafter is decided by the treating physician.
    Study Design
    Go to sections
    Study Type : Interventional (Clinical Trial)
    Estimated Enrollment : 100 participants
    Allocation: Randomized
    Intervention Model: Parallel Assignment
    Intervention Model Description:
    Patients will be on the study for a total of 5 months, this includes 4 months on active study intervention, with breast surgery at week 16 and one month follow up period, after surgery. Patients will be randomly assigned to one of the following arms. 1. Anti-PD1 antibody pembrolizumab (Keytruda, Merck) will be infused day 12, at the standard dose of 200 mg IV over 30 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity. 2. FLT3L (CDX-301, the recombinant human protein by Celldex) will be self-administered subcutaneously, in 5 consecutive daily injections, week 1, day 1-5.

    3. For all arms radiation therapy to the breast tumor will begin on week 2 (Day 8,10,12), at dose of 8 Gy x 3 fractions, every other day. 4. Letrozole (Femara ®, Novartis) 2.5 mg tabs, once a day, daily for 4 months, until surgery, and thereafter is decided by the treating physician

    Masking: None (Open Label)
    Masking Description:
    Patients will be randomly assigned to one of the following arms. 1. Anti-PD1 antibody pembrolizumab (Keytruda, Merck) will be infused day 12, at the standard dose of 200 mg IV over 30 minutes, repeated every 3 weeks until disease progression or unacceptable toxicity. 2. FLT3L (CDX-301, the recombinant human protein by Celldex) will be self-administered subcutaneously, in 5 consecutive daily injections, week 1, day 1-5.

    3. For all arms radiation therapy to the breast tumor will begin on week 2 (Day 8,10,12), at dose of 8 Gy x 3 fractions, every other day. 4. Letrozole (Femara ®, Novartis) 2.5 mg tabs, once a day, daily for 4 months, until surgery, and thereafter is decided by the treating physician

    Primary Purpose: Treatment
    Official Title: Converting HR+ Breast Cancer Into an Individualized Vaccine
    Actual Study Start Date : March 17, 2020
    Estimated Primary Completion Date : December 30, 2021
    Estimated Study Completion Date : December 30, 2023
  • I
    Ignatz
    The initial Phase 1 study using a subcutaneous formulation of CDX-0159 has a planned study completion date of this month. Since the subcutaneous formulation will support the initiation of later stage studies this year, these results are vitally important.

    The company has been strangely silent since the first subcutaneous dosing in September.
  • s
    sal
    Does anyone have any news why sp tanked today?
  • M
    Morgan
    ARNA buyout today--market cap 5.5B. We have Arena's entire pipeline and more in our CDX-0159!
  • M
    Metalmeister
    CLDX was $900 in 1987?
  • A
    Anonymous
    CDX-0159 clinical news:

    """Dec 8, 2021
    Celldex Announces First Patient Dosed in Phase 1 Study of CDX-0159 in Prurigo Nodularis
    HAMPTON, N.J., Dec. 08, 2021 (GLOBE NEWSWIRE) -- Celldex Therapeutics, Inc. (NASDAQ:CLDX) today announced that the first patient has been dosed in a Phase 1 study of CDX-0159 for the treatment of prurigo nodularis (PN). CDX-0159 is a humanized monoclonal antibody that specifically binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. PN is a chronic skin disease that causes hard, intensely itchy lumps/nodules to form on the skin. The itching (pruritus) can be intense, causing people to scratch themselves to the point of bleeding or pain, which can form lesions and perpetuate the disease cycle.

    “The initiation of this study represents a significant milestone in the clinical development of CDX-0159 and its exciting potential to impact diseases with mast cell involvement,” said Diane C. Young, MD, Senior Vice President and Chief Medical Officer of Celldex Therapeutics. “Research suggests mast cells play an important role in amplifying chronic itch and neuroinflammation in PN and we believe CDX-0159 has the potential to disrupt these pathways. PN is an often severe and debilitating disease with a significant impact on quality of life for patients and currently no approved treatment options. We look forward to advancing this program along with the rest of our clinical pipeline.”

    The randomized, double-blind, placebo-controlled, Phase 1 study is evaluating CDX-0159 in patients with prurigo nodularis. Approximately 40 patients will be enrolled across 4 parallel groups and treated for 8 weeks (1.5 mg/kg dose every 4 weeks, 3.0 mg/kg single dose followed by placebo 4 weeks later, 4.5 mg/kg single dose followed by placebo four weeks later and placebo dose every 4 weeks) with 10 patients in each group. Patients will be followed for 16-weeks after dosing. The primary endpoints of the study are safety and tolerability; secondary endpoints include clinical effect, pharmacokinetics and pharmacodynamics. For additional information on this trial (NCT04944862), please visit www.clinicaltrials.gov.

    About Prurigo Nodularis
    Prurigo nodularis (PN) is a skin disease that causes hard, itchy lumps (nodules) to form on the skin. The itching (pruritus) can be intense, causing people to scratch themselves to the point of bleeding or pain, which can form lesions and perpetuate the disease cycle. Scratching can cause more skin lesions to appear. The itching is worsened by heat, sweating, or irritation from clothing. Diagnosis of the disease is based on observing signs such as extremely itchy skin with the formation of nodules. In some cases, a skin biopsy is used to confirm the diagnosis. There are currently no approved therapies for prurigo nodularis.

    About CDX-0159
    CDX-0159 is a humanized monoclonal antibody that specifically binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. KIT is expressed in a variety of cells, including mast cells, which mediate inflammatory responses such as hypersensitivity and allergic reactions. KIT signaling controls the differentiation, tissue recruitment, survival and activity of mast cells. In certain inflammatory diseases, such as chronic urticaria, mast cell activation plays a central role in the onset and progression of the disease.""""
  • I
    Ignatz
    Well, now that's curious. Up 7.5% on almost 3X normal volume on a down day for the markets.
  • A
    ALPP
    CLDX + IQST Up 50 % week + AABB Up 1,185 % yr + VSBGF AI Security + ALPP
  • M
    Mick
    Free fall?
  • l
    longvrts
    Report out: inhibition of mast cells mitigates hypersensitivity reactions due to anti-drug antibodies induced by biologicals. Given the widespread use of biologicals- in fact the biggest blockbusters currently are biologicals- this is another substantial market for an effective anti-inflammatory like CDX-0159:

    Front Immunol . 2021 Nov 1;12:765747. doi: 10.3389/fimmu.2021.765747. eCollection 2021.

    How to Prevent and Mitigate Hypersensitivity Reactions to Biologicals Induced by Anti-Drug Antibodies?

    Alessandra Vultaggio 1, Margherita Perlato 2, Francesca Nencini 1, Emanuele Vivarelli 1, Enrico Maggi 3, Andrea Matucci 1
    Affiliations expand
    PMID: 34790200 PMCID: PMC8591239 DOI: 10.3389/fimmu.2021.765747
    Free PMC article

    Abstract
    Biologicals are widely used therapeutic agents for rheumatologic diseases, cancers, and other chronic inflammatory diseases. They are characterized by complex structures and content of variable amounts of foreign regions, which may lead to anti-drug antibodies (ADA) development. ADA onset may limit the clinical usage of biologicals because they may decrease their safety. In fact they are mainly associated with immediate hypersensitivity reactions (HSRs). Development of ADAs is reduced by concomitant immunosuppressive treatment, while it is increased by longer intervals between drug administrations; thus, regular infusion regimens should be preferred to reduce HSRs. Once ADAs have formed, some procedures can be implemented to reduce the risk of HSRs. ADAs may belong to different isotype; the detection of IgE ADA is advisable to be assessed when high and early ADAs are detected, in order to reduce the risk of severe HRs. In patients who need to reintroduce the biological culprit, as alternative therapies are not available, drug desensitization (DD) may be applied. Desensitization should be conceptually dedicated to patients with an IgE-mediated HSR; however, it can be performed also in patients who had developed non-IgE-mediated HSRs. Although the underlying mechanisms behind successful DD has not been fully clarified, the DD procedure is associated with the inhibition of mast cell degranulation and cytokine production. Additionally, some data are emerging about the inhibition of drug-specific immune responses during DD.

    Keywords: IgE; anaphylaxis; anti-drug antibodies; drug desensitization; hypersensitivity reactions; immunogenicity.
  • A
    Anonymous
    Any news from the conference this morning?
  • s
    sal
    Jan 1992 SP was over $1300
  • t
    tom
    Gambling.all biotech are an if they come up with something
  • P
    Peter
    For every seller at this level, there's a buyer who is playing a longer game. I think that we all know how that game is going to end, so this is just a little bump in the bigger picture.
  • M
    Morgan
    CDX-0159 being formulated in SQ form!!!! This means all the indications longv has cited literature on can be treated as an outpatient $$$$ just like Dupixent $$$$.
  • l
    longvrts
    Report out: Mast cells cause liver damage and fibrosis. One more significant indication added to the long list of diseases where an effective mast cell inhibitor is urgently needed. CDX-0159 anti-inflammatory mast cell inhibitor is best-in-class and has demonstrated robust efficacy and safety in clinical trials:

    Hepatology. 2021 Nov;74(5):2684-2698. doi: 10.1002/hep.32028. Epub 2021 Sep 9.

    Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling

    Vik Meadows 1 2, Lindsey Kennedy 2, Burcin Ekser 3, Konstantina Kyritsi 2, Debjyoti Kundu 2, Tianhao Zhou 2, Lixian Chen 2, Linh Pham 2, Nan Wu 2, Jennifer Demieville 4, Laura Hargrove 4, Shannon Glaser 4, Gianfranco Alpini 1 2, Heather Francis 1 2

    PMID: 34164827 DOI: 10.1002/hep.32028
    Full text linksCite

    Abstract
    Background and aims: Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)/FGF15. Patients with primary sclerosing cholangitis (PSC) typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis. In bile-duct-ligated (BDL) MC-deficient mice (B6.Cg-KitW-sh /HNihrJaeBsmJ [KitW-sh ]), ductular reaction (DR) and liver fibrosis decrease compared with BDL wild type, and MC injection exacerbates liver damage in normal mice.

    Approach and results: In this study, we demonstrated that MC-FXR regulates biliary FXR/FGF15, DR, and hepatic fibrosis and alters intestinal FXR/FGF15. We found increased MC number and biliary FXR expression in patients with liver injury compared with control. Histamine and FGF19 serum levels and small heterodimer partner expression increase in patients PSC and PSC-IBD compared with healthy controls. MC injection increased liver damage, DR, inflammation, biliary senescence/senescence-associated secretory phenotype (SASP), fibrosis, and histamine in KitW-sh mice. Inhibition of MC-FXR before injection reduced these parameters. BDL and KitW-sh mice injected with MCs displayed increased TBA content, biliary FXR/FGF15, and intestinal inflammation, which decreased in BDL KitW-sh and KitW-sh mice injected with MC-FXR. MCs increased ileal FXR/FGF15 expression in KitW-sh mice that was reduced following FXR inhibition. BDL and multidrug resistance 2/ATP-binding cassette family 2 member 4 knockout (Mdr2-/- ) mice, models of PSC, displayed increased intestinal MC infiltration and FXR/FGF15 expression. These were reduced following MC stabilization with cromolyn sodium in Mdr2-/- mice. In vitro, MC-FXR inhibition decreased biliary proliferation/SASP/FGF and hepatic stellate cell activation.

    Conclusions: Our studies demonstrate that MC-FXR plays a key role in liver damage and DR, including TBA regulation through alteration of intestinal and biliary FXR/FGF15 signaling.
  • L
    Libor
    Less than 300 shares this morning trying hard to appear like its the end of the world. It’s not. $CLDX =$80 buy out target
  • V
    VONHEIMLER
    Didn't marucci say he was going to announce a new Indication for 0159? Did that happen yet?