monoclonal antibodies

An Oral Interleukin-23–Receptor Antagonist Peptide for Plaque Psoriasis

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Abstract

Background

The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23–receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production.

Methods

In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16.

Results

A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose–response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups.

Conclusions

After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23–receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis.

Monoclonal Antibodies With Focused Ultrasound May Slow Alzheimer Disease Progression

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A promising clinical study in the treatment of Alzheimer disease leveraged focused ultrasound (FUS) technology to open the blood-brain barrier with delivery of a systemic monoclonal antibody infusion, enhancing the removal of cerebral beta-amyloid, a hallmark of Alzheimer disease. This innovative treatment approach shows promise in enhancing targeted drug delivery in Alzheimer disease and other neurological conditions.

The study, conducted with WVU Rockefeller Neuroscience Institute (RNI) and reported in the latest issue of The New England Journal of Medicine, presents encouraging benefits for Alzheimer disease patients. Researchers at RNI collaborated with Insightec, a manufacturer of FUS technology.

“Focused ultrasound provides a new opportunity for Insightec collaborations with drug companies to improve drug delivery to the brain,” says Maurice R. Ferré, MD, Insightec’s CEO and chairman of the board. “Only 1-2% of drugs can cross the blood-brain barrier, making progress difficult and patient safety challenging when using large systemic drug concentrations. The ability to disrupt the blood-brain barrier to effectively deliver treatment demonstrates the power and potential of using focused ultrasound technology when addressing complex neurological conditions.”

“The results from this proof-of-concept study are encouraging and chart a path forward to improve drug delivery in combating Alzheimer disease,” said Ali Rezai, MD, executive chair of RNI. “Our long-time close collaboration with Insightec has helped accelerate advances in treatment of patients with Alzheimer disease and other neurological diseases.”

Alzheimer disease is a condition that affects 6.7 million Americans today –and promising new therapies are emerging to address this unmet medical need. This latest breakthrough discovery opens up new avenues for research and provides renewed hope for patients and their loved ones. As research progresses, it is anticipated that this treatment approach will continue to evolve and refine, paving the way for even more effective treatments.

How do monoclonal antibodies work against cancer?

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Monoclonal antibodies are immune system proteins that are created in the lab. Antibodies are produced naturally by your body and help the immune system recognize germs that cause disease, such as bacteria and viruses, and mark them for destruction. Like your body’s own antibodies, monoclonal antibodies recognize specific targets.

Many monoclonal antibodies are used to treat cancer. They are a type of targeted cancer therapy, which means they are designed to interact with specific targets.

Some monoclonal antibodies are also immunotherapy because they help turn the immune system against cancer. For example, some monoclonal antibodies mark cancer cells so that the immune system will better recognize and destroy them. An example is rituximab, which binds to a protein called CD20 on B cells and some types of cancer cells, causing the immune system to kill them. B cells are a type of white blood cell.

Other monoclonal antibodies bring T cells close to cancer cells, helping the immune cells kill the cancer cells. An example is blinatumomab (Blincyto®), which binds to both CD19, a protein found on the surface of leukemia cells, and CD3, a protein on the surface of T cells. This process helps the T cells get close enough to the leukemia cells to respond to and kill them.

a monoclonal antibody brings a t cell close to the cancer cell
Some monoclonal antibodies bring t cells close to cancer cells, helping them kill cancer cells.

Which cancers are treated with monoclonal antibodies?

Many monoclonal antibodies have been approved to treat a wide variety of cancers.

To learn about specific treatments for your cancer, see the PDQ® adult cancer treatment summaries and childhood cancer treatment summaries.

What are the side effects of monoclonal antibodies?

Monoclonal antibodies can cause side effects, which can differ from person to person. The ones you may have and how they make you feel will depend on many factors, such as how healthy you are before treatment, your type of cancer, how advanced it is, the type of monoclonal antibody you are receiving, and the dose.

Doctors and nurses cannot know for sure when or if side effects will occur or how serious they will be. So, it is important to know which signs to look for and what to do if you start to have problems.

Like most types of immunotherapy, monoclonal antibodies can cause skin reactions at the needle site and flu-like symptoms.

Needle site reactions include:

  • pain
  • swelling
  • soreness
  • redness
  • itchiness
  • rash

Learn more about skin changes caused by cancer treatment.

Flu-like symptoms include:

  • chills
  • fatigue
  • fever
  • muscle aches and pains
  • nausea
  • vomiting
  • diarrhea

Learn more about flu-like symptoms caused by cancer treatment.

Monoclonal antibodies can also cause:

  • mouth and skin sores that can lead to serious infections
  • high blood pressure
  • congestive heart failure
  • heart attacks
  • inflammatory lung disease

Monoclonal antibodies can cause mild to severe allergic reactions while you are receiving the drug. In rare cases, the reaction is severe enough to cause death.

Some monoclonal antibodies can also cause capillary leak syndrome. This syndrome causes fluid and proteins to leak out of tiny blood vessels and flow into surrounding tissues, resulting in dangerously low blood pressure. Capillary leak syndrome may lead to multiple organ failure and shock.

Cytokine release syndrome can sometimes occur with monoclonal antibodies, but it is often mild. Cytokines are immune substances that have many different functions in the body, and a sudden increase in their levels can cause:

  • fever
  • nausea
  • headache
  • rash
  • rapid heartbeat
  • low blood pressure
  • trouble breathing

How Monoclonal Antibodies Treat Cancer

Learn how monoclonal antibodies such as trastuzumab, pembrolizumab, and rituximab are used to treat cancer.

Monoclonal antibodies ineffective for omicron no longer authorized in US

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The FDA halted the use of two monoclonal antibody treatments for COVID-19 because they are not effective against the omicron variant of SARS-CoV-2, which now accounts for almost all U.S. cases.

The FDA revised the emergency use authorizations for the two treatments bamlanivimab and etesevimab administered together, and the cocktail of casirivimab and imdevimab. Their use will now be limited to infections that are likely to have been caused by a variant that is susceptible to the treatments.

Source: Adobe Stock.
The FDA revised the emergency use authorizations for two monoclonal antibody therapies to limit their use to patients who likely to have been infected with a variant that is susceptible to the treatments. Source: Adobe Stock.

“Because data show these treatments are highly unlikely to be active against the omicron variant, which is circulating at a very high frequency throughout the United States, these treatments are not authorized for use in any U.S. states, territories, and jurisdictions at this time,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release.

Cavazzoni said this will avoid exposing patients to side effects from treatments “that are not expected to provide benefit to patients who have been infected with or exposed to the omicron variant.”

She said the treatments may be reauthorized in regions where patients are likely to be infected or exposed to a susceptible variant, or if they are proven affective against future variants.

The FDA noted that there are several other therapies that are expected to work against omicron, including Paxlovid, sotrovimab, remdesivir and molnupiravir.

“Health care providers should consult the NIH panel’s COVID-19 treatment guidelines and assess whether these treatments are right for their patients,” Cavazzoni said.

Targeting Interleukin-17 in Patients With Active Rheumatoid Arthritis.

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Abstract

Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti- IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.

Source: Medscape.com

 

<}� t� �5� -family:”Arial Unicode MS”,”sans-serif”; border:none windowtext 1.0pt;mso-border-alt:none windowtext 0in;padding:0in’>n = 35) while the other half had no personal or family history of a psychiatric disorder, including substance abuse (n = 30). Assessments were made of eating behavior and dietary food intake, estimation of body composition, and measurement of plasma leptin. Although cocaine users reported significantly higher levels of dietary fat and carbohydrates as well as patterns of uncontrolled eating, their fat mass was significantly reduced compared with their non-drug using peers. Levels of leptin were associated with fat mass, and with the duration of stimulant use. Tobacco smoking status or concomitant use of medication did not affect the significance of the results. Weight changes in cocaine users reflect fundamental perturbations in fat regulation. These are likely to be overlooked in clinical practice but may produce significant health problems when cocaine use is discontinued during recovery.

 

 

What are biosimilars and are they important?

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Abstract

All prescribers will be familiar with the issues associated with the use of branded and generic ‘chemical’ medicines.1 For biological products (e.g. epoetin, filgrastim), a biosmilar medicine is a new biological product that is similar to a medicine that has already been authorised to be marketed in the EU (the biological reference medicine).2 Six biosimilar medicinal products are currently marketed in the UK—three versions of filgrastim (▼Nivestim, ▼Tevagrastim and Zarzio),3–5 two versions of epoetin (Binocrit and Retacrit)6,7 and one version of somatropin (Omnitrope).8 Applications for biosimilar versions of follitropin alfa and infliximab are under evaluation by the European Medicine’s Agency (EMA) Committee for Medicinal Products for Human Use.9 In the future there may also be biosimilar versions of insulins, recombinant vaccines, interferons and monoclonal antibodies such as rituximab and trastuzumab.10 It is estimated that about 50% of the current UK market for biological medicines by spend may be subject to biosimilar competition by 2019. In this article, we will consider the background to developing biosimilar medicines, how and why they differ from traditional generic medicines in their licensing requirements and the issues that may arise as they are introduced to clinical practice.

Source: BMJ

 

 

What is Radioimmunotherapy (RIT) Treatment of NHL?

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Radioimmunotherapy (RIT) is a type of targeted therapy that delivers radiation directly to cancer cells. It combines a monoclonal antibody—a type of protein that recognizes and binds to certain parts of cancer cells—with radioactive material. When the monoclonal antibody binds to the cancer cell, the radiation kills the cell.

Currently, RIT is used for the treatment of B-cell non-Hodgkin lymphomas (see examples below). RIT is also being evaluated for the treatment of other types of cancer, including prostate cancer and glioblastoma.

RIT is given on an outpatient basis, is generally completed in 10 days (as opposed to the longer duration of conventional chemotherapy), and avoids many of the side effects of chemotherapy. Because RIT may result in a temporary reduction in blood cell counts, patients typically need to have their blood cell levels monitored after treatment.

Examples of RIT

Zevalin® (ibritumomab tiuxetan): Zevalin therapy combines the monoclonal antibody Rituxan® (rituximab) with Zevalin, which is comprised of an anti-CD20 monoclonal antibody and Yttrium-90, a radioisotope that delivers the radiation. When injected into the body, Zevalin attaches to a protein (CD20) found only on the surface of B-lymphocytes, such as cancerous B-cells found in many forms of non-Hodgkin’s lymphoma. The radioactivity that is spontaneously emitted targets the B-cell and destroys it. This approach protects healthy tissue.  To learn more about Zevalin and view stories from other patients living with follicular lymphoma go to www.Zevalin.com. To locate a Zevalin-experienced oncologist click here.

Bexxar® (tositumomab and iodine I 131 tositumomab): Bexxar also targets B lymphocytes, and is comprised of an anti-CD20 monoclonal antibody and radioactive iodine 131. Bexxar is used for the treatment of certain patients with CD20-positive relapsed or refractory non-Hodgkin lymphoma.

Zevalin and Advanced Follicular Lymphoma

Researchers conducted a study that included 414 patients with CD20-positive stage III or IV follicular lymphoma who achieved a complete or partial response after first-line induction treatment. Patients were randomly assigned to receive Zevalin or no further treatment.

After a median follow-up of 3.5 years, the results indicated that Zevalin significantly prolonged median progression-free survival (PFS) in all patients, regardless of whether they had achieved a partial or complete response. Median PFS in patients treated with Zevalin was 36.5 months, compared to 13.3 months for patients in the control group. For patients who achieved a partial response after induction treatment, those who received Zevalin had a median PFS of 29.3 months compared to 6.2 months for those in the control group. Among patients who achieved complete response after induction, those who received Zevalin had a median PFS of 53.9 months compared to 29.5 months in the control group. What’s more, 77 percent of patients who experienced a partial response after induction converted to a complete response, which resulted in a final complete response rate of 87 percent.

The researchers concluded that Zevalin significantly prolonged PFS and resulted in a high conversion rate from partial to complete response, regardless of the type of first-line induction treatment.

Reference:

Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. Journal of Clinical Oncology. 2008; 26: 5156-5164.

 

Source: cancerconnect.com

New Insights About Trastuzumab for HER2-Positive Early Breast Cancer

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Substantial benefits persisted at 4-year follow-up and were also seen in patients who crossed over to trastuzumab.

The benefits of trastuzumab are well established for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (whether early or advanced). The current standard is 1 year of trastuzumab therapy, but the optimal duration of treatment in the adjuvant setting remains unknown. The Herceptin Adjuvant (HERA) trial is an ongoing international, multicenter, randomized, phase III trial involving >5000 women with HER2-positive, early stage breast cancer who completed local regional therapy (surgery with or without radiation therapy) and at least 4 cycles of chemotherapy (adjuvant, neoadjuvant, or both). Patients were randomly assigned to observation or trastuzumab for 1 or 2 years. At median follow-up of 1 year, disease-free survival (DFS) was significantly better in patients who received trastuzumab than in those who did not (hazard ratio, 0.54); thus, the trial protocol was amended to allow crossover for patients without recurrence who did not receive trastuzumab initially. Subsequent analysis at median follow-up of 2 years showed that, compared with chemotherapy alone, the addition of trastuzumab was associated with better DFS (HR, 0.64) and overall survival (OS; HR, 0.66; JW Oncol Hematol Feb 5 2007).

Now, HERA investigators report data on trastuzumab versus observation at median follow-up of 4 years in an analysis that incorporated the effect of crossover from observation to trastuzumab. The study population included 1698 patients initially randomized to observation and 1703 patients to trastuzumab for 1 year.

Intent-to-treat (ITT) analysis of DFS showed a substantial benefit in the trastuzumab group versus observation (4-year DFS: 78.6% vs. 72.2%; HR, 0.76); however, ITT analysis of OS showed no significant difference in risk for death (4-year OS: 89.3% and 87.7%; HR, 0.85). In all, 885 of 1698 patients in the observation group (52%) ultimately crossed over to trastuzumab, beginning treatment a median of 22.8 months after initial randomization. DFS outcomes in these patients were substantially better than in those who remained on observation.

Comment: These results reaffirm that the addition of trastuzumab significantly improves outcomes of patients with early stage, HER2-positive breast cancer. A more nuanced view discloses additional insights. Most trials have shown incremental improvement in survival with concurrent chemotherapy plus trastuzumab as opposed to the sequential approach in the HERA trial. The HERA trial also suggests that late administration of trastuzumab (i.e., long after adjuvant chemotherapy has been completed) can confer significant benefit to patients who did not receive trastuzumab at the outset of treatment. However, such an approach is unlikely to be adopted or tested in prospective clinical trials because standard of care dictates that anti-HER2 therapy be instituted soon after completion of local therapy.

— William J. Gradishar, MD

Published in Journal Watch Oncology and Hematology