Pharmapoet

Tag: mAb

  • Teclistamab Mechanism of Action. Twice more Powerful

    I am Taclistamab, designed in the lab,
    A mighty bi-specific mAb.
    One end binds cancer, holding it tight,
    One end finds T-cells to join the fight.
    I help the immune system take its aim,
    And snipe myeloma, ending its game.

    How Taclistamab helps Immune System to fight Myeloma

    Teclistamab is a new approach of cancer treatment. It has two targets:

    1. CD3 receptor of an immune cell, called T lymphocyte or simply T-cell
    2. B-cell maturation antigen (BCMA) receptors on the surface some cancers, particularly myeloma cells (multiple myeloma).
    Taclistamab bi-specific antibody

    Taclistamab belongs to the broader group of biothechnology drugs, called monoclonal antibodies.

    Scientists refer monoclonal antibodies (mAbs), which can bind two targets simultaneously bispecific mAbs.

    Being bispecific can significantly boost your therapeutic value:

    1. One side of a protein can recognise a cancer
    2. Another can attach to T-cell, which fights this type of cancer

    When you bridge two cells toghether, T-cell would recognise adversary immediately and release cytotoxic chemicals to destoy cancer. The release of cancer DNA and proteins alerts other nearby cells, guiding them directly to the cancer site.

    Talistamab can initiate a strong, self-sustained immune response against multiple myeloma. It makes a drug is crucial for both advanced stage of disease or cases where cancer is resistant to the other more conventional type of treatments.

    Multiple myeloma

    Your bones has tissue, called “bone marrow”. It is a main factory of all blood cells: red (erythrocytes), white (leucocytes), and platelets (thrombocytes).

    Healthy bone marrow illustration
    Healthy bone marrow produces red and white blood cells and platelets

    Normally, your bone marrow produces 100 billion white blood cells each day to protect the body form intruders. Most of them venture to the blood, lymphoid tissues, and other organs. However, one type never leaves the area – B-cells would mature and turn inot the plasma cells. Plasma cells stay in bone marrow.

    Plasma cells are bulky, have a lifespan of 2-3 days, and produce an anourmous number of antibodies. Their main function is to learn about a foe and produce a specific proten to fight it.

    Multiple myeloma is a cancer of plasma cells. Unlike their normal counterparts, myeloma cells exhibit several distinct characteristics:

    • They aggresively multiply through cell division. As their number and volume increases, the pressure builds inside the tight spaces within the leading to pain,bone destructuion, and fractures.
    • They can hijack the supply chain redirecting the blood flow and nutrients to fuel their growth, depriving healthy tissues of the bone marrow. Clinically, it will manifest as an anemia and an immune difficiency.
    • They fabricate abnormal antibodies, called M-protein. M-protein is a junk and doesn’t fight infections. Kidneys try to keep up eliminating it, but at certain levels it would turn into the amyloid deposites in various organs, leading to organ failures.
    Myeloma cells redirects the blood flow and

    Teclistamab Background

    • Teclistamab is a bispecific monoclonal antibody against multiple myeloma.
    • It is classified as a bi-specific T-Cell engager (BiTe)
    • On October 25, 2022, FDA granted accelerated approval to teclistamab-cqyv 
    • It was developed by Janssen Biotech, Inc under the name TECVAYLI®

    Clinical Trials

    FDA granted an accelerated approval based on the clinical trial MajesTEC-1 (NCT03145181; NCT04557098), a single-arm, multi-cohort, open-label, multi-center study.

    Patients, who had previously received at least four more conventional therapies for myeoloma (and still relapsed) have been given the taclistamab. Among 110 in the treatment group, 61.8% acheived a partial or complete remission.

    Mechanism of Action

    The drug targets the B-cell maturation antigen (BCMA) on malignant plasma cells and CD3 on T cells.

    CD3 is protein specific to normal T-cells. It has three chains with the longest having a similar structure to antibody. Tha’s why CD3 belongs to antibody superfamily.

    It triggers an initiall stage of immune reaction, so many scientists consider it “a gas or a brakes” of an immune cascade.

    Step 1. Activation of T-Cells

    Upon binding to CD3, T-cells undergo activation, leading to several crucial responses:

    • Increase in cytokine production, especially interferon-gamma and tumor necrosis factor-alpha.
    • Being cytotoxic, different cytokines recruite even more immune cells to the cancer site.

    Once several cancer cells are destroyed and their by-products enter the bloodstream, more immune cells get attracted by the myeloma site. Scientists call this phenomena amplification of immune response.

    This amplification of the immune response is essential for improving therapeutic outcomes but also reponsible for serous side effects, such as Cytokine release syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).

    Step 2. Binding to the Myeloma Cell

    BCMA is a valid theraupeutic target, as health plasma cells do not usually express them, while myeloma cells enjoy this “decorum” on their membraines. BCMA helps cancer cell to survive and proliferate.

    Taclistamab cancer demise

    The activation and proliferation of T-cells lead to a direct cytotoxic effect on myeloma cells. Once activated, T-cells release perforins and granzymes, inducing apoptosis in targeted cancer cells.

    The localized action of teclistamab allows for effective tumor cell elimination while sparing surrounding healthy tissue. This targeted approach maximizes therapeutic benefits and minimizes adverse effects, contributing to an effective treatment for multiple myeloma.

    Clinical use of Teclistamab

    Teclistamab plays a significant role in treating multiple myeloma, particularly for patients with limited treatment options. This section outlines its place in therapy and the recommended treatment regimen.

    Place of Teclistamab in Myeloma Treatment

    Teclistamab is indicated for patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy:

    • liproteasome inhibitors;
    • immunomodulatory agents;
    • anti-CD38 therapies.

    The drug targets B-cell maturation antigen (BCMA), which is critical myeloma life cycle. Solid results from the clinical trials inspire an optimism among researchers and clinicians, suggesting they may soon have a tool to target resistant cancer — a potential breakthrough.

    Treatment Regimen and Dosage

    Teclistamab is typically administered via subcutaneous (under the skin) injection. The initial dose is 1500 µg, followed by maintenance doses of 750 µg.

    Dosing is conducted every week for the first month and then once every two weeks. It’s essential to monitor for potential adverse effects, which may include cytokine release syndrome (CRS).

    Careful patient selection and monitoring can help maximize the benefits of teclistamab while minimizing risks. Regular follow-ups ensure timely management of side effects and dosage adjustments if necessary.

    Teclistamab Side Effects

    Teclistamab can lead to a variety of side effects. Understanding these effects is crucial for managing them effectively during treatment.

    Cytokine Release Syndrome

    Cytokine Release Syndrome (CRS) is a common reaction associated with Teclistamab. It occurs when the immune system is activated rapidly upon exposure to the drug.

    You may experience symptoms ranging from mild to severe.

    Common symptoms include:

    • Fever
    • Chills
    • Nausea
    • Fatigue
    • Headache

    Severe cases can lead to hypotension and difficulty breathing. Monitoring for signs of CRS is essential, particularly in the days following administration.

    CRS Symptoms

    Symptoms of CRS can manifest quickly, often within hours of treatment. Early recognition is key to managing this reaction.

    Mild symptoms may resolve with supportive care.

    Severe reactions might require treatment interventions such as corticosteroids or anti-inflammatory medications. If symptoms worsen, it is vital to contact your healthcare provider immediately.

    Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

    Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is another serious potential side effect of Teclistamab. This condition can affect the central nervous system and may occur concurrently with CRS.

    Symptoms typically include confusion, difficulty speaking, or seizures. The severity of ICANS can vary, and monitoring is crucial.

    If you notice any neurological changes, communicate these to your healthcare team.

    Management may involve steroid treatment or close observation depending on severity. Your doctor will determine the best approach based on your specific situation.

    Teclistamab and Future of Myeloma Treatment

    Teclistamab represents a significant advance in myeloma treatment. It targets both B-cell maturation antigen (BCMA) and CD3, engaging T-cells to attack myeloma cells.

    Key Benefits:

    • Dual-target mechanism: By targeting BCMA, teclistamab effectively directs the immune response against malignant plasma cells.
    • Durable responses: Early studies suggest that this therapy can lead to prolonged remission in patients with previously treated myeloma.

    Clinical Trials:

    Ongoing trials are investigating teclistamab’s efficacy and safety compared to standard treatments. These studies are crucial for understanding its role in the treatment landscape.

    Considerations for Clinicians:

    • Combination therapies: Teclistamab may be used in combination with other treatments, enhancing its effectiveness.
    • Diverse patient populations: It is being tested across various stages of myeloma, which may broaden its applicability.

    Future Implications:

    As more data emerges, teclistamab could redefine treatment protocols. Its innovative approach may lead to new standards of care in managing myeloma, offering more avenues for relapsing and resistant cases of this cancer.

    Summary of mechanism of Action of Taclistamab

    Teclistamab has two binding sites, that brings two cells toghether:

    • Our foe, containing BCMA (B-cell maturation antigen)
    • Our friend, expressing CD3 on T-cells

    This dual-targeting capability allows the antibody to bridge the gap between T-cells and malignant cells effectively.

    This bridging facilitates a localized immune response, directing T-cells precisely where they are needed. The specialized design of teclistamab enhances its ability to engage the immune system directly against tumor cells while minimizing damage to normal tissues.

  • Lecanemab Mechanism of Action: the First Alzheimer’s Drug that Works?

    Lecanemab Mechanism of Action: the First Alzheimer’s Drug that Works?

    Lecanemab is an IgG1 monoclonal antibody that binds and eliminates building blocks of amyloid plaques in the brain, thus helping to slow progression of Alzheimer disease.

    Lacenemab: Discovery and Approval

    Lecanemab (brand name Leqembi) was discovered by BioArctic, a Swedish biopharmaceutical company, in collaboration with Eisai Co., Ltd.

    Since 2005 the team of Swedish biotech company BioArctic has been looking for a potential “cleaner of beta-amyloid protein deposits” in the brain. Previous studies have shown that beta-amyloid protein, which scientists believe to be “a brain junk“, plays a crucial role in the progression of Alzheimer’s disease.

    Beta amyloid plaques

    At the start, lecanemab showed promising results in removing amyloid plaques in the brain. With phase II trials lecanemab showed main virtue of the sucessful meidication:

    “the larger was a dose of the lecanemab; the better was the effect in removing amyloid debris”

    The pivotal Phase III trial, known as Clarity AD cemented potential status as first Alzheimer’s breakthrough with 27% slowdown of disease progression comparing with placebo after 18 month of treatment.

    Key Approval Timeline:

    • July 2022: FDA granted Priority Review
    • January 6, 2023: Received accelerated approval from the FDA
    • July 6, 2023: Gained traditional FDA approval based on Phase III results

    The FDA’s traditional approval represented a significant milestone as one of the first disease-modifying treatments for Alzheimer’s disease. Regulatory agencies in Japan and China approved lecanemab in September and December 2023, respectively.

    The European Medicines Agency (EMA) followed with approval in early 2024, expanding global access to this novel treatment approach for early Alzheimer’s disease.

    Normal and Alzheimer's cell

    Lecanemab in Alzheimer Disease

    Lecanemab represents a significant advancement in Alzheimer’s disease treatment through its targeted approach to amyloid beta aggregation. Recent clinical trials have demonstrated its efficacy in slowing cognitive decline in early-stage Alzheimer’s disease patients.

    What is Alzheimer?

    Alzheimer’s disease (AD) also known as Alzheimer dementia accounts for 80% of all cases of memory loss. It affects approximately 6.5 million Americans and is projected to nearly triple by 2060 as the population ages. There are three main features of AD:

    • The decline of cognitive abolities is serious enough to interfere with daily activities
    • AD is progressive disorder, so it worsens over time
    • There is no cure for the Alzheimer’s dementia and till the recent years there was no reliable medication to slow the progression of this dibilitating disease
    Alzheimer's brain

    Changes in Alzheimer’s Brain

    Now let’s take a microscope and look at the AD’s brain tissues. There are two main “hystological landmarks” that you don’t usually see in normal brains:

    • amyloid beta plaques, discovered by no other than Dr. Alois Alzheimer
    • tau neurofibrillary tangles, not as speciifc, as the amyloid debris, as tangles are found in other neurological disorders called taupaties, but stiil a significant biomarker of AD.

    Apart of playing a role of “biomarkers”, which help to diagnose the disease, these protein aggregates have a significant role in development and progression of AD.

    Role of Amyloid Beta

    Amyloid beta (Aβ) is a soluble protein found in healthy brain cells. Although scientists are still puzzling out what it is, evidence suggests it might help neurons to grow and survive. Some researchers believe it has anti-cancer activities and helps glia cells (neural babysitters) to repulse infections and pathogens.

    As in many molecules, Aβ has different forms: some of them good and some of them not. A low level of Aβ-42 in blood and CFS, and a high level of Aβ-40 is certainly toxic for our brain and are associated with cognitive decline. The test measuring their ratio in the blood is approved in the USA as an early biomarker of Alzheimer’s disease.

    Toxic Aβ residues bind each other forming a toxic soluble component called oligomer. Many labs developed a test to measure the level of the Aβ Oligomer as an early marker of AD.

    Beta Amyloid Pathway

    Amyloid oligomers continue to aggegragate forming protofibril – main target of lecanemab, which is also an intermidiary product in so called “Amyloid aggregation pathway”. Still soluble, several protofibrils form a mature fibril, which precipitates and forms a an amyloid debris.

    Life of neural cells gets significantly distrupted by amyloid junk:

    • It slows down neural impulses
    • It attract attention of the immune system, that promotes inflammation of the neurons
    • It disrupts neaural recovery and stresses out neural cells

    Previous Attempts to Target Amyloid

    Solanezumab is a humanized monoclonal IgG1 antibody directed against amino acids13–28 of amyloid. It recognizes soluble monomeric Aβ and does not recognize amyloid plaques. The drug has been tested both in sporadic and familial AD patients and failed to show any clinical improvement.

    Crenezumab binds oligomeric and fibrillar Aβ with high affinity, promising

    Gantenerumab is a fully human IgG1 antibody that binds Aβ fibrils. It has two epitopes on Aβ: one in the N-terminal region (amino acids 3–11) and another in the central region (amino acids 18–27). Clinical trials showed it is 8% more effective than placebo, which is disappointing.

    Second-generation antibodies like aducanumab showed more promise. However, conflicting trial results and concerns about amyloid-related imaging abnormalities (ARIA) complicated its regulatory path.

    Several gamma-secretase inhibitors also failed in trials due to off-target effects and safety concerns. Beta-secretase inhibitors similarly disappointed, highlighting the complexity of targeting the amyloid pathway effectively.

    Lecanemab in Action

    Amyloid-beta Targeting

    Lecanemab is an IgG1 monoclonal antibody that selectively binds to soluble Aβ protofibrils. The precise binding site is still a secret, but studies hint it lies between amino acids 1 and 15 of Aβ.

    The antibody binds with high affinity to amyloid-beta protofibrils, creating immune complexes that can be cleared through various elimination pathways:

    • Microglia cells, which combine functions of bodyguard and babysitter for neurons, would devour fibrills marked by the Lecamab
    • Direct neutralization of toxic protofibrils by antibodies

    How effective is lecanemab for Alzheimer’s disease

    Clinical trials have demonstrated significant efficacy for lecanemab in early Alzheimer’s disease. The phase 3 CLARITY-AD trial showed a 27% slowing of cognitive decline compared to placebo over 18 months, as measured by the Clinical Dementia Rating Scale.

    Lecanemab and dendritic cells

    Biomarker studies confirm lecanemab substantially reduces amyloid plaques 65-80% as shown during pet imaging of patients receiving lecanemab.

    The drug demonstrates greater efficacy when administered on early stages of the disease, particularly in patients with mild cognitive impairment or early signs of AD. Treatment benefits appear dose-dependent.

    Despite measurable benefits, lecanemab does not halt disease progression completely. Treatment effects are relatively modest in terms of slowing rates of cognitive decline, resulting in 4-6 month delay in symptom progression.

    How Would you Take Lecanemab

    The doctors administer lecanemab via I.V. route. Medical supervision is must, as studies showed 28% of patients receiving lecanemab compalined post-injection complications.

    Before you take lecanemab

    Patients should undergo comprehensive medical evaluation before starting lecanemab treatment. This includes brain MRI scans to assess for amyloid-related imaging abnormalities (ARIA) and to establish a baseline for monitoring.

    Genetic testing for APOE ε4 allele status may be recommended, as carriers have a higher risk of developing ARIA. Healthcare providers should review the patient’s complete medication list to identify potential interactions.

    Patients with a history of cerebral hemorrhage, unstable cardiovascular disease, or certain autoimmune conditions may not be suitable candidates. A thorough discussion about potential benefits and risks should take place before initiating treatment.

    Medical professionals must ensure patients understand the commitment to regular infusions and monitoring appointments. Patients should report any new neurological symptoms immediately during treatment.

    Does Lecanemab interact with other medications

    Lecanemab may interact with anticoagulant and antiplatelet medications, potentially increasing the risk of cerebral hemorrhage. Patients taking warfarin, direct oral anticoagulants, or antiplatelet drugs require careful monitoring.

    Combinations of monoclonal antibodies targeting amyloid has not been studied and is not recommended. Potential interactions with cholinesterase inhibitors and memantine (common Alzheimer’s medications) appear minimal based on available data.

    Medications that affect the immune system might theoretically impact lecanemab’s efficacy, though clinical evidence is limited.

    Is it Safe to Take Lecanemab?

    Safety concerns with lecanemab primarily revolve around amyloid-related imaging abnormalities (ARIA) and practical monitoring requirements for patients undergoing treatment.

    Previous trials show

    The pivotal Phase 3 CLARITY-AD trial provided crucial safety data for lecanemab. Among 898 participants receiving the drug, approximately 21.3% developed ARIA-E (edema) compared to 9.3% in the placebo group. Most ARIA-E cases were asymptomatic, detected only through routine MRI monitoring.

    ARIA-H (hemorrhage) occurred in 17.3% of lecanemab-treated participants versus 9.0% in the placebo group. The trial reported 0.7% mortality in both treatment and placebo arms, suggesting no significant increase in death rate.

    Safety monitoring included regular MRIs during the first 14 weeks of treatment. APOE ε4 carriers showed higher ARIA risk, with 30.8% of homozygotes developing ARIA-E compared to 13.2% in non-carriers.

    Potential side effects

    Infusion-related reactions represent another significant concern, affecting 26.4% of lecanemab recipients compared to 7.4% in the placebo group. These reactions typically manifest as flu-like symptoms, headache, or nausea during or shortly after administration.

    Most infusion reactions occur during early treatments and diminish with subsequent doses. Premedication with antihistamines, antipyretics, or corticosteroids may help manage these reactions.

    Other reported side effects include headache (17%), falls (17%), and diarrhea (9%). Serious adverse events occurred in 14% of lecanemab-treated participants versus 11% in the placebo group.

    Long-term safety data remains limited as the longest clinical trials lasted 18 months. Ongoing monitoring through registry studies and post-approval surveillance will provide critical information about rare side effects and long-term safety profiles.

    Other promissing drugs to treat Alzheimer

    While Lecanemab offers a promising approach to treating Alzheimer’s disease, several other therapeutic candidates are in various stages of development. These emerging treatments target different pathological mechanisms and aim to either slow disease progression or alleviate symptoms through novel pathways.

    Potential Therapeutic targets for Alzheimer disease

    Tau protein aggregation represents a significant therapeutic target beyond amyloid. Anti-tau antibodies like Zagotenemab and Semorinemab aim to prevent tau tangles formation and spread. Though recent trials have shown mixed results, ongoing research continues to refine these approaches.

    Neuroinflammation modulation offers another promising avenue. Drugs targeting microglial activation, such as GC021109 and masitinib, show potential by dampening inflammatory responses in the brain that contribute to neurodegeneration.

    Metabolic dysfunction correction through drugs like T3D-959, which targets PPAR delta/gamma pathways, addresses glucose metabolism abnormalities common in Alzheimer’s patients. This approach recognizes the “type 3 diabetes” hypothesis of Alzheimer’s disease.

    Neuroprotective strategies utilizing compounds like Blarcamesine (ANAVEX2-73) aim to activate sigma-1 receptors, potentially reducing oxidative stress and improving cellular resilience. Early clinical trials have shown promising cognitive benefits.

    Current Alzheimer pipeline

    Donanemab, developed by Eli Lilly, has shown promising results in Phase 3 trials with significant plaque reduction and slowed cognitive decline. It received Breakthrough Therapy designation from the FDA in 2021.

    Gantenerumab, while failing to meet primary endpoints in pivotal trials, continues development with modified dosing strategies. Swiss pharma giant Roche remains committed to exploring its potential benefits.

    ACI-35 represents a novel vaccine approach targeting pathological tau. This immunotherapy stimulates antibody production against phosphorylated tau without triggering harmful autoimmune responses.

    Small molecule approaches include SAGE-718, an NMDA receptor modulator showing improvements in executive function in early trials. PQ912, a glutaminyl cyclase inhibitor, aims to reduce production of pyroglutamate-modified Aβ, a particularly toxic form.

    Non-pharmaceutical treatment of Alzheimer disease

    Cognitive stimulation therapy (CST) provides structured activities designed to enhance cognitive function and social interaction. Multiple studies demonstrate moderate improvements in cognition and quality of life when delivered in group settings.

    Physical exercise programs show remarkable benefits with aerobic activities like walking potentially slowing cognitive decline. Research indicates 150 minutes of moderate exercise weekly may help maintain cognitive function.

    Dietary interventions, particularly the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay), have shown promising results. This approach emphasizes leafy greens, berries, nuts, and limits red meat and processed foods.

    Multimodal approaches combining lifestyle interventions yield synergistic benefits. The FINGER study demonstrated that simultaneous nutritional guidance, exercise, cognitive training, and vascular risk monitoring significantly reduced cognitive decline compared to single interventions.

    Summary

    Lecanemab is a monoclonal antibody designed to target and remove amyloid beta (Aβ) plaques in Alzheimer’s disease. It specifically binds to soluble Aβ protofibrils, which are considered more neurotoxic than other forms of amyloid aggregates.

    The drug works through immunotherapy principles by recognizing the N-terminus of Aβ protofibrils with high selectivity. This binding gives a signal to glia to clear amyloid plaques.

    Clinical trials have demonstrated lecanemab’s effectiveness in reducing amyloid plaque burden by approximately 27% compared to placebo groups. PET imaging studies confirm significant reductions in brain amyloid levels following treatment.

    The mechanism involves three key steps:

    • selective binding to protofibrils,
    • recruitment of microglia,
    • clearance of Aβ aggregates.

    This targeted approach minimizes interactions with monomeric Aβ, which may have physiological functions in the brain.

    Lecanemab’s specificity distinguishes it from earlier anti-amyloid antibodies. By focusing on protofibrils rather than all amyloid forms, it satnds out as a safer and more specific option.

    The drug’s concentration in brain circulation is 500 time less of its level in peripheral blood. Although it might seem to be poor result for any small molecule, lecanemab crosses blood brain barrier much better than other representatives of the class.