Tadekinig Alfa for Cytokine Release Syndrome

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Pennsylvania

Disqualifiers: Pregnant, Nursing, Hypersensitivity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 5 days

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a pilot, open-label study to assess the safety and feasibility of using investigational drug(s) as rescue therapies for CAR T cell related CRS and HLH-like syndrome (CRHLS).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Tadekinig alfa for treating cytokine release syndrome?

Research shows that IL-18 binding protein, the active component in Tadekinig alfa, effectively blocks IL-18, a molecule involved in inflammation, by forming a strong bond with it. This has been demonstrated to reduce inflammation in conditions like sepsis, suggesting it may help manage cytokine release syndrome by reducing excessive inflammatory responses. ^{1 2 3 4 5}

Is Tadekinig Alfa (IL-18BP) generally safe for humans?

Research on IL-18 binding protein, including studies on mice, suggests it is generally safe, as transgenic mice with high levels of IL-18BP showed no tissue or organ abnormalities and were protected against inflammatory stimuli. ^{2 5 6 7 8}

How does the drug Tadekinig Alfa work differently for cytokine release syndrome?

Tadekinig Alfa is unique because it targets and neutralizes interleukin-18 (IL-18), a protein involved in inflammation, by using a binding protein that acts as a decoy receptor. This approach is different from other treatments as it specifically prevents IL-18 from interacting with its receptor, reducing inflammation without affecting other pathways. ^{2 3 6 9 10}

Eligibility Criteria

This trial is for adults over 18 who are already part of a University of Pennsylvania CAR T cell study. They must be able to have children and agree to use birth control as described in the protocol. Pregnant or nursing women, or those allergic to the drug's ingredients, cannot join.

Inclusion Criteria

Signed, written informed consent

Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol

I am 18 years old or older.

Exclusion Criteria

Known hypersensitivity to the active substance or one of the excipients of the investigational product(s)

Pregnant or nursing (lactating) women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Tadekinig alfa injections as rescue therapy for CAR T cell related CRS and HLH-like syndrome

5 days

3 visits (in-person)

Continued Dosing (Optional)

Continued dosing approximately every 48-72 hours if the subject is responsive to initial therapy but has ongoing symptoms

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 days

Treatment Details

Interventions

• Tadekinig alfa (IL-18BP)

Trial Overview The study is testing Tadekinig alfa (IL-18BP) as a rescue therapy for severe immune reactions called CRS and HLH-like syndrome that can happen after CAR T cell treatments. It's an early-stage trial to see if it's safe and workable.

Participant Groups

Group I: Tadekinig alfa Experimental Treatment 1 Intervention

* Injection #1/Day 1: As clinically indicated in accordance with Figure 1.1-1. * Repeat Injection(s): Missed doses will not be made up. * Injection #2/Day 3: Approximately 48 hours (+/- 5 hours) after receipt of the 1st injection. * Injection #3/Day 5: Approximately 48 hours (+/- 5 hours) after receipt of the 2nd injection. * Continued Dosing (Optional): Approximately q48-72 hours; If the subject is responsive to initial therapy, but has ongoing symptoms of CRS/CRHLS. * Retreatment (Optional): May be considered

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

The study successfully cloned and expressed interleukin-18 binding protein from both mice and humans, demonstrating its potential as a therapeutic target.

Both recombinant interleukin-18 binding proteins effectively inhibited interleukin-18 from binding to its receptor and reduced IFN-gamma production, suggesting they may act as antagonists to interleukin-18.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cloning and expression of interleukin-18 binding protein. Aizawa, Y., Akita, K., Taniai, M., et al.[2019]

The human interleukin-18-binding protein (hIL-18BP) effectively inhibits the proinflammatory cytokine IL-18 by binding to it, which could be crucial for developing treatments for inflammatory diseases.

Research identified seven key amino acids in hIL-18BP that significantly affect its binding affinity to IL-18, with tyrosine 97 and phenylalanine 104 being particularly important, potentially guiding the design of new molecular antagonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the functional epitopes of human interleukin-18-binding protein by site-directed mutagenesis. Xiang, Y., Moss, B.[2021]

IL-18 binds to its receptor IL-18R alpha/beta complex, which has a high affinity for IL-18, and this binding is crucial for activating immune responses, including the activity of NK and T cells.

A specific neutralizing antibody, 125-2H, can inhibit IL-18 binding to IL-18R alpha, but not to the alpha/beta complex, suggesting that the receptor's structure changes upon dimerization, which is important for signal transduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-18 receptor beta-induced changes in the presentation of IL-18 binding sites affect ligand binding and signal transduction. Wu, C., Sakorafas, P., Miller, R., et al.[2019]

IL-18 binding protein (IL-18BP) effectively inhibits the proinflammatory cytokine IL-18 by forming a stable complex, which is crucial in regulating inflammation, especially in conditions like sepsis.

In septic patients, serum levels of IL-18BP were significantly elevated (21.9 ng/ml) compared to healthy individuals (2.15 ng/ml), indicating its potential role in managing IL-18 activity during severe infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Novick, D., Schwartsburd, B., Pinkus, R., et al.[2022]

IL-18 is a pro-inflammatory cytokine linked to various inflammatory and cardiovascular diseases, and its activity can be inhibited by IL-18 binding protein (IL-18BP), which has a higher affinity for IL-18 than the IL-18 receptor.

This study is the first to examine the biological activity of recombinant human Fc-IL-18BPc, showing its potential to inhibit IL-18-induced cytokines like IFNγ and IL-6, suggesting a promising therapeutic avenue for conditions involving IL-18.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant Fc-IL-18BPc isoform inhibits IL-18-induced cytokine production. Hong, K., Oh, K., Lee, S., et al.[2012]

Interleukin-18 binding protein (IL-18BP) acts as a decoy receptor that effectively inhibits the functions of IL-18, which is important in inflammatory diseases and cancers.

Gene expression of IL-18BP is significantly increased in response to interferon-gamma (IFN-gamma) in various human cell types, suggesting a negative feedback mechanism that regulates IL-18 activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Mühl, H., Kämpfer, H., Bosmann, M., et al.[2022]

IL-18 is a key cytokine involved in autoimmune diseases and cancer, and its activity is regulated by IL-18-binding protein (IL-18BP), which creates a feedback loop that can complicate the assessment of IL-18's biological activity.

Accurate measurement of both active IL-18 and IL-18BP is crucial for understanding disease activity and for developing targeted anti-IL-18 therapies, highlighting the need for advanced techniques to assess these biomarkers in various biological samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of Free Bioactive IL-18 and IL-18BP in Inflammatory Disorders. Fauteux-Daniel, S., Girard-Guyonvarc'h, C., Caruso, A., et al.[2023]

Transgenic mice expressing high levels of human IL-18 binding protein (IL-18BP) were found to be viable and fertile, with no organ abnormalities, indicating that IL-18BP is safe for use in vivo.

These IL-18BP-Tg mice showed significantly reduced inflammatory responses, including lower levels of IFN-gamma and protection against liver damage in inflammatory models, demonstrating the efficacy of IL-18BP in modulating immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation and characterization of mice transgenic for human IL-18-binding protein isoform a. Fantuzzi, G., Banda, NK., Guthridge, C., et al.[2008]

Interleukin-18 binding protein (IL-18BP) acts as a soluble antagonist that regulates immune responses by binding to IL-18 ligands, preventing them from activating their receptors on cell membranes, which is crucial for balancing Th1 and Th2 cytokine responses.

IL-18BP is distinct from other IL-18 receptors and is being studied in clinical trials for its potential therapeutic role in autoimmune diseases, highlighting its importance in immune regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases. Park, SY., Hisham, Y., Shin, HM., et al.[2022]

A newly discovered interleukin 18 binding protein (IL18BP) effectively neutralizes IL18, which is crucial for regulating immune responses, particularly by suppressing interferon gamma production.

Two specific human isoforms of IL18BP demonstrated high affinity for IL18, neutralizing over 95% of its activity, suggesting their potential as therapeutic agents in diseases where IL18 plays a role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting interleukin 18 with interleukin 18 binding protein. Dinarello, CA.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Cloning and expression of interleukin-18 binding protein. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Determination of the functional epitopes of human interleukin-18-binding protein by site-directed mutagenesis. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

IL-18 receptor beta-induced changes in the presentation of IL-18 binding sites affect ligand binding and signal transduction. [2019]

4. England pubmed.ncbi.nlm.nih.gov

A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Recombinant Fc-IL-18BPc isoform inhibits IL-18-induced cytokine production. [2012]

6. United States pubmed.ncbi.nlm.nih.gov

Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Detection of Free Bioactive IL-18 and IL-18BP in Inflammatory Disorders. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Generation and characterization of mice transgenic for human IL-18-binding protein isoform a. [2008]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Targeting interleukin 18 with interleukin 18 binding protein. [2019]