IC14 for Heart Failure
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Implicit Bioscience
Must be taking: Loop diuretics
Must not be taking: Immunosuppressives, Anti-inflammatories
Disqualifiers: Acute coronary syndromes, Uncontrolled hypertension, Active infection, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?The goal of this clinical trial is to learn if drug atibuclimab (IC14) works to treat adults hospitalized with acute decompensated heart failure (ADHF). It will also learn about the safety of IC14. The main questions it aims to answer are:
Is the drug IC14 safe in patients with ADHF? What are the IC14 drug levels in the bloodstream after treatment with IC14? What is the impact of IC14 treatment on markers of disease in the bloodstream? What is the impact of IC14 treatment on measures of heart failure? There is no placebo arm in this study.
Participants will:
Take drug IC14 once via an intravenous infusion After the infusion, be visited in the hospital or visit the clinic 5 times for checkups and tests Answer questions about their medical status via a phone call 3 months after the infusion
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you have used immunosuppressive or anti-inflammatory drugs recently, you may not be eligible to participate.
What data supports the effectiveness of the drug Atibuclimab (IC14, Anti-CD14 antibody) for heart failure?
Research suggests that the immune system plays a significant role in heart failure, and targeting immune components like CD14 could be beneficial. Elevated levels of soluble CD14 are linked to poor outcomes in heart failure, indicating that targeting CD14 with treatments like Atibuclimab might help improve heart failure conditions.
12345Is Atibuclimab (IC14) safe for human use?
The research articles focus on immune checkpoint inhibitors (ICIs) and their potential heart-related side effects, such as myocarditis (inflammation of the heart muscle) and other cardiovascular issues. While these articles do not specifically mention Atibuclimab (IC14), they highlight the importance of monitoring for heart-related side effects when using similar treatments.
678910What makes the drug Atibuclimab unique for treating heart failure?
Atibuclimab is unique because it is an anti-CD14 antibody, which targets a specific protein involved in immune response, potentially offering a novel mechanism of action compared to traditional heart failure treatments that typically focus on managing symptoms or improving heart function.
1112131415Eligibility Criteria
This trial is for adults hospitalized with acute decompensated heart failure (ADHF). Participants must be currently admitted for ADHF to qualify. Specific inclusion and exclusion criteria details are not provided, but typically these would outline the health status and other conditions that either qualify or disqualify a person from participating.Inclusion Criteria
Patients must be symptomatic for moderate to severe dyspnea, have received or scheduled to receive intravenous loop diuretics, be at least 21 years old, willing to provide informed consent, have screening plasma C-reactive protein levels >3 mg/L, and use effective contraception if of childbearing potential
I was hospitalized for worsening heart failure, experiencing shortness of breath, and have a weak heart pump.
Exclusion Criteria
I do not have severe heart failure, major health issues, recent surgeries, or use medications that could interfere with the study.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
Treatment
Participants receive a single intravenous infusion of IC14 and are monitored for safety and efficacy
1 day
1 visit (in-person)
Monitoring
Participants are monitored in the hospital or clinic for safety and efficacy, including biomarker and pharmacokinetic assessments
10 days
5 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including a phone call assessment
3 months
1 visit (virtual)
Participant Groups
The trial is testing atibuclimab (IC14), administered once via IV infusion, to treat ADHF. It aims to assess the safety of IC14, its levels in the bloodstream post-treatment, its effect on disease markers in blood, and how it impacts heart failure measures. There's no placebo comparison; all participants receive IC14.
1Treatment groups
Experimental Treatment
Group I: IC14 (atibuclimab)Experimental Treatment1 Intervention
20 mg/kg intravenously once at baseline
Atibuclimab is already approved in United States for the following indications:
🇺🇸 Approved in United States as Atibuclimab for:
- Acute Decompensated Heart Failure (clinical trial phase, not yet approved)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of VirginiaCharlottesville, VA
Virginia Commonwealth UniversityRichmond, VA
Loading ...
Who Is Running the Clinical Trial?
Implicit BioscienceLead Sponsor
Virginia Commonwealth UniversityCollaborator
University of VirginiaCollaborator
References
Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults. [2022]CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.
Immunomodulation and immunopharmacology in heart failure. [2023]The immune system is intimately involved in the pathophysiology of heart failure. However, it is currently underused as a therapeutic target in the clinical setting. Moreover, the development of novel immunomodulatory therapies and their investigation for the treatment of patients with heart failure are hampered by the fact that currently used, evidence-based treatments for heart failure exert multiple immunomodulatory effects. In this Review, we discuss current knowledge on how evidence-based treatments for heart failure affect the immune system in addition to their primary mechanism of action, both to inform practising physicians about these pleiotropic actions and to create a framework for the development and application of future immunomodulatory therapies. We also delineate which subpopulations of patients with heart failure might benefit from immunomodulatory treatments. Furthermore, we summarize completed and ongoing clinical trials that assess immunomodulatory treatments in heart failure and present several therapeutic targets that could be investigated in the future. Lastly, we provide future directions to leverage the immunomodulatory potential of existing treatments and to foster the investigation of novel immunomodulatory therapeutics.
Circulating immune checkpoints predict heart failure outcomes. [2023]There are limited data examining the role of immune checkpoint (IC) ligands in the pathophysiology of heart failure (HF). Therefore, we explore this in three HF animal models and in three different human cohorts (healthy, stable, and worsening HF).
Effects of therapy using the Celacade system on structural and functional cardiac remodelling in rats following myocardial infarction. [2021]Immune modulation by the Celacade system (Vasogen Inc, Canada) decreases mortality and hospitalization in human heart failure.
[Update on therapy of chronic heart failure. Innovations and studies from last year]. [2018]Chronic heart failure is one of the most common chronic diseases worldwide with increasing prevalence and incidence. Due to the high morbidity and mortality a standardized and evidence-based therapy is crucial. The present review article gives an overview about the innovations in 2014 based on the current guidelines of the European Society of Cardiology. First, improvements in established medication regimens regarding beta blockers and mineralocorticoid receptor antagonists as well as treatment options for heart rate reduction will be explained. Second, new pharmacological developments, such as angiotensin receptor neprilysin inhibition will be discussed. Finally, new insights into common comorbidities of patients with chronic heart failure, such as atrial fibrillation and hyperkalemia will be presented.
The role of immune checkpoints in cardiovascular disease. [2022]Immune checkpoint inhibitors (ICI) are monoclonal antibodies which bind to immune checkpoints (IC) and their ligands to prevent inhibition of T-cell activation by tumor cells. Currently, multiple ICI are approved targeting Cytotoxic T-lymphocyte antigen 4 (CTLA-4), Programmed Death Protein 1 (PD-1) and its ligand PD-L1, and Lymphocyte-activation gene 3 (LAG-3). This therapy has provided potent anti-tumor effects and improved prognosis for many cancer patients. However, due to systemic effects, patients can develop immune related adverse events (irAE), including possible life threatening cardiovascular irAE, like atherosclerosis, myocarditis and cardiomyopathy. Inhibition of vascular IC is associated with increased atherosclerotic burden and plaque instability. IC protect against atherosclerosis by inhibiting T-cell activity and cytokine production, promoting regulatory T-cell differentiation and inducing T-cell exhaustion. In addition, PD-L1 on endothelial cells might promote plaque stability by reducing apoptosis and increasing expression of tight junction molecules. In the heart, IC downregulate the immune response to protect against cardiac injury by reducing T-cell activity and migration. Here, inhibition of IC could induce life-threatening T-cell-mediated-myocarditis. One proposed purpose behind lymphocyte infiltration is reaction to cardiac antigens, caused by decreased self-tolerance, and thereby increased autoimmunity because of IC inhibition. In addition, there are several reports of ICI-mediated cardiomyopathy with immunoglobulin G expression on cardiomyocytes, indicating an autoimmune response. IC are mostly known due to their cardiotoxicity. However, t his review compiles current knowledge on mechanisms behind IC function in cardiovascular disease with the aim of providing an overview of possible therapeutic targets in prevention or treatment of cardiovascular irAEs.
Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week. [2020]Immune checkpoint inhibitors (ICIs) have been an important therapeutic advance in the field of cancer medicine, resulting in a significant improvement in survival of patients with advanced malignancies. Recent reports provided greater insights into the incidence of cardiovascular adverse events (CVAEs) with ICI use. Myocarditis is the most common CVAE associated with ICI. Pericardial diseases, Takotsubo syndrome, arrhythmias, and vasculitis constitute other significant AEs. Physicians should be aware of these infrequent, but potentially fatal toxicities associated with ICIs as their therapeutic use becomes widespread with a myriad of approvals by the U.S. Food and Drug Administration. Management involves prompt administration of high-dose corticosteroids and discontinuation of ICIs in severe myocarditis. This review summarizes the most updated evidence on epidemiology, pathophysiological mechanisms, and management strategies of various CVAEs associated with ICIs. Highlights from recent guidelines published by National Comprehensive Cancer Network on ICI-related CV toxicities have also been incorporated.
Cardiotoxicity associated with immune checkpoint inhibitors: Current status and future challenges. [2022]Immune checkpoint inhibitors (ICIs) are the most notable breakthrough in tumor treatment. ICIs has been widely used in tumor patients, but its wide range of immune-related adverse events (irAEs) should not be ignored. irAEs can be involved in any organ system, including immune-related cardiotoxicity. Although the cardiotoxicity induced by immune checkpoint inhibitors is rare, it is extremely lethal and has attracted increasing attention. PD-1 and PD-L1 are expressed in human cardiomyocytes, so the application of PD-1/PDL-1 inhibitors can cause many adverse reactions to the cardiovascular system. This review summarizes the latest epidemiological evidence on the cardiovascular toxicity of programmed cell death protein-1(PD-1)/programmed cell death ligand-1(PD-L1) inhibitors and the clinical manifestations, as well as the potential pathological mechanisms. These updates may provide a novel perspective for monitoring early toxicity and establishing appropriate treatment for patients with ICI-related cardiotoxicity.
Immune Checkpoint Inhibitors: Cardiotoxicity in Pre-clinical Models and Clinical Studies. [2021]Since the approval of the first immune checkpoint inhibitor (ICI) 9 years ago, ICI-therapy have revolutionized cancer treatment. Lately, antibodies blocking the interaction of programmed cell death protein (PD-1) and ligand (PD-L1) are gaining momentum as a cancer treatment, with multiple agents and cancer types being recently approved for treatment by the US Food and Drug Administration (FDA). Unfortunately, immunotherapy often leads to a wide range of immune related adverse events (IRAEs), including several severe cardiac effects and most notably myocarditis. While increased attention has been drawn to these side effects, including publication of multiple clinical observational data, the underlying mechanisms are unknown. In the event of IRAEs, the most widely utilized clinical solution is administration of high dose corticosteroids and in severe cases, discontinuation of these ICIs. This is detrimental as these therapies are often the last line of treatment options for many types of advanced cancer. In this review, we have systematically described the pathophysiology of the PD-1/PD-L1 axis (including a historical perspective) and cardiac effects in pre-clinical models, clinical trials, autoimmune mechanisms, and immunotherapy in combination with other cancer treatments. We have also reviewed the current challenges in the diagnosis of cardiac events and future directions in the field. In conclusion, this review will delve into this expanding field of cancer immunotherapy and the emerging adverse effects that should be quickly detected and prevented.
A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety. [2022]Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1 and induce the activation of the immune system against cancer. Despite the efficacy of ICIs, which has improved the oncotherapy for patients with a variety of malignancies, several immune-related adverse events (irAEs) have been described, including those affecting the heart. Cardiac irAEs after ICI therapies, including myocarditis, can become life-threatening, and their pathogenic mechanisms remain unclear. Here, a systematic analysis was performed regarding the potential immune mechanisms underlying cardiac irAEs based on the immune adverse events induced by the ICIs: 1) recruitment of CD4+ and CD8+ T cells, 2) autoantibody-mediated cardiotoxicity, and 3) inflammatory cytokines. Furthermore, the impact of dual therapies in ICI-induced cardiac irAEs and the potential risk factors are reviewed. We propose that self-antigens released from cardiac tissues or cancer cells and the severity/advancement of cancer disease have an important role in ICI cardiotoxicity.
Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity. [2023]Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.
Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. [2017]Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. The aim of this study was to characterize B cell immunosuppression mediated by the Fc-engineered antibody, XmAb5871, which coengages FcγRIIb with the B cell antigen receptor (BCR) complex and that is currently in clinical development for the treatment of rheumatoid arthritis (RA). Because rheumatoid factor (RF) might interfere with the binding of XmAb5871 to FcγRIIb, we correlated RF titers with the potency of XmAb5871.
Use of a novel camelid-inspired human antibody demonstrates the importance of MMP-14 to cancer stem cell function in the metastatic process. [2019]Matrix metalloproteinases (MMPs) are considered excellent targets for cancer therapy because of their important roles in multiple aspects of tumor growth and metastatic spread. However, not all MMPs, or even all activities of specific MMPs, promote cancer. Therefore, there is a need for highly specific inhibitors. Monoclonal antibodies provide the potential for the degree of specificity required, but the isolation of antibodies able to inhibit a specific protease with high selectivity is challenging. Proteolysis specificity lies in recognition of the substrate in or around the active site, which generally forms a concave cleft inaccessible by human IgGs. Inspired by camelid antibodies, which have convex paratopes, we have produced a recombinant human IgG, designated 3A2, which binds in the substrate cleft of MMP-14, inhibiting its activity, but not the activity of highly homologous MMPs. In the 4T1 highly metastatic, syngeneic, orthotopic model of breast cancer, IgG 3A2 markedly inhibited growth of the primary tumor, but more importantly reduced metastatic spread to the lungs and liver by 94%. Stem cells in the tumor population expressed twice as much MMP-14 mRNA as bulk tumor cells. In addition to reducing dissemination of tumor stem cells, as would be expected from inhibition of MMP-14's ability to degrade components of the extracellular matrix, IgG 3A2 also inhibited the ability of individual stem cells to proliferate and produce colonies. We conclude that it is possible to produce antibodies with sufficient specificity for development as therapeutics and that IgG 3A2 has therapeutic potential.
Monoclonal antibody 14C5 targets integrin alphavbeta5. [2020]This study identifies and characterizes the antigen recognized by monoclonal antibody (mAb) 14C5. We compared the expression of antigen 14C5 with the expression of eight integrin subunits (alpha1, alpha2, alpha3, alphav, beta1, beta2, beta3, and beta4) and three integrin heterodimers (alphavbeta3, alphavbeta5, and alpha5beta1) by flow cytometry. Antigen 14C5 showed a similar expression to alphavbeta5 in eight different epithelial cancer cell lines (A549, A2058, C32, Capan-2, Colo16, HT-1080, HT-29, and SKBR-3). Specific binding of P1F6, an anti-alphavbeta5 specific antibody, was blocked by mAb 14C5. After transient expression of alphavbeta5 in 14C5-negative Colo16 cells, mAb 14C5 was able to bind a subpopulation of alphavbeta5-positive cells. We evaluated the tissue distribution of the 14C5 antigen in colon (n = 20) and lung (n = 16) cancer tissues. The colon carcinoma cells stained positive for 14C5 in 50% of tumors analyzed, whereas bronchoalveolar lung carcinoma and typical carcinoid were not positive for the antigen. More common types of non-small cell lung cancer, i.e., squamous (n = 5) and adenocarcinoma (n = 3), stained positive in 2 of 5 squamous carcinomas and in 1 of 3 investigated adenocarcinoma. Colon (95%) and lung (50%) carcinoma tissues showed extensive expression of antigen 14C5 in the stroma surrounding the tumor cells and on the membrane of the adjacent fibroblasts. We show for the first time that mAb 14C5 binds the vascular integrin alphavbeta5, suggesting that mAb 14C5 can be used as a screening agent to select colon and lung cancer patients that are eligible for anti-alphavbeta5-based therapies.
Human Fcγ receptors compete for TGN1412 binding that determines the antibody's effector function. [2020]The first-in-human clinical trial of the CD28-specific monoclonal antibody (mAb) TGN1412 resulted in a life-threatening cytokine release syndrome. Although TGN1412 was designed as IgG4, known for weak Fc:Fcγ receptor (FcγR) interactions, these interactions contributed to TGN1412-induced T-cell activation. Using cell lines (TFs) expressing human FcγRI, -IIa, -IIb, or -III, we show that TGN1412 and TGN1412 as IgG1 and IgG2 are bound by FcγRs as it can be deduced from literature. However, upon coculture of TGN1412-decorated T cells with TFs or human primary blood cells, we observed that binding capacities by FcγRs do not correlate with the strength of the mediated effector function. FcγRIIa and FcγRIIb, showing no or very minor binding to TGN1412, mediated strongest T cell proliferation, while high-affinity FcγRI, exhibiting strong TGN1412 binding, mediated hardly any T-cell proliferation. These findings are of biological relevance because we show that FcγRI binds TGN1412, thus prevents binding to FcγRIIa or FcγRIIb, and consequently disables T-cell proliferation. In line with this, FcγRI- FcγRII+ but not FcγRI+ FcγRII+ monocytes mediate TGN1412-induced T-cell proliferation. Collectively, by using TGN1412 as example, our results indicate that binding of monomeric IgG subclasses does not predict the FcγR-mediated effector function, which has major implications for the design of therapeutic mAbs.