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  • Pertuzumab Mechanism of Action. New Hope – Old target

    Table of Contents

    Scientists and researchers have their odd ways of solving problems, and when they team up with one of the biggest biotech companies, their ideas can go beyond research papers—and become real-world solutions we get to see.

    Brief History of Pertuzumab

    Pertuzumab (Parjeta) is a clear example of a scientific and marketing genius. It entered the market in 2012 to treat breast cancer in combination with Herceptin (trastuzumab) and one of the taxenes (a group of chemotherapeutic agents).

    So what is so interesting about pertuzumab?

    Genentech has marketed Herceptin (Trastuzumab) in 1998. It was a scientific and clinical breakthrough. Trastuzumab became the first monoclonal antibody to target the HER-2 receptor on the surface of the cancer cells. It made the company billions of dollars and cemented itself as a standard of care.

    Trastuzumab secret

    Although Herceptin delivered the expectation of improving clinical outcomes for many patients with breast cancer, scientists were particularly unsettled with one trastuzumab issue – they do not exactly know how it works!

    Trastuzumab and HER2

    Trastuzumab binds the Human Epidermal Growth factor Receptor-2 ( HER-2), which is found in every fifth case of breast cancer. Breast cancer cells express HER-2 to survive, grow, and spread, which makes HER-2 an attractive target for targeted agents and chemotherapy.

    The tigh has formed, but the process, which follows next is still a subject of the scientific debate. The research community has identified four most probable scenarios:

    • It stops the process of heterodimerization of HER-2;
    • It adds phosphorus to the HER-2 protein;
    • It facilitates the removal of the HER-2 from the cell surface;
    • It attracts immune cells that destroy cancer.

    Heterodimerization

    HER-2 is a unique protein in the family of four tyrosine kinases. All representatives exist in two forms:

    • Monomer or inactive form.
    • Dimer form or active form. The dimer is essentially two monomers bonded together.

    HER-2 cannot cannot bind another HER-2, it can only bind other members of the family (usually HER-1 or HER-3). The process is called heterodimerization, and it is crucial for activating cancer growth, expansion, and

    Another way, scientists thought Herceptin works is by invoking a phosphorylation of the HER-2 receptor. Phosphorylation is adding a phosphorus residue to one of the amino acids (usually tyrosine). Phosphorylation makes HER-2 less stable and overall leads to a better prognosis for cancer patients.

    More recent studies suggest that trastuzumab facilitates endocytosis of the HER-2 receptor – the cancer cells just swallow their receptors removing it from the surface.

    Finally, some scientists believe trastuzumab binds the HER-2 receptor and “calls” the immune system to fight cancer cells. This theory is supported by microscopic evidence – cancer tissues treated with trastuzumab, were heavily infiltrated by different immune cells.

    Pertuzumab is an “open book” for researchers.

    Similar to trastuzumab, pertuzumab is a monoclonal antibody, that binds HER-2 receptor. Unlike its “enigmatic friend, trastuzumab’s mechanism of action is clear – upon binding the target, it prevents dimerization of HER-2.

    Pertuzumab in action

    Pertuzumab Basics

    Pertuzumab is a humanized monoclonal antibody primarily used in cancer therapy. It targets the HER2 receptor, playing a crucial role in inhibiting tumor growth in HER2-positive breast cancer. Understanding its classification and properties helps in appreciating its impact on treatment.

    Classification and Overview

    Pertuzumab is classified as a recombinant humanized monoclonal antibody. It specifically targets the extracellular domain II of the HER2 receptor.

    This mechanism blocks dimerization with other HER family receptors, inhibiting downstream signaling pathways. Pertuzumab is used in combination with trastuzumab and chemotherapy to enhance therapeutic efficacy.

    It is particularly effective in treating metastatic breast cancer and has been shown to improve survival rates in patients.

    Chemical and Biological Properties

    Pertuzumab has a molecular weight of approximately 148 kDa. It is composed of 4 heavy chains and 4 light chains, which form its unique structure.

    The drug is produced using recombinant DNA technology in Chinese hamster ovary cells. Pertuzumab’s stability and half-life allow for effective dosing in clinical settings.

    Administration is typically via intravenous infusion, with dosages tailored to the patient’s specific needs. Understanding these properties is essential for optimizing its therapeutic use.

    Mechanism of Action

    Pertuzumab acts through a specific mechanism involving multiple interactions with HER2 receptors, playing a significant role in cancer treatment. Its primary functions include binding to HER2 receptors, inhibiting dimerization, and enhancing immune responses.

    Binding to HER2 Receptors

    Pertuzumab binds selectively to the extracellular domain of the HER2 receptor. This process blocks the receptor’s ability to interact with other molecules involved in cell signaling.

    The binding alters how cancer cells receive growth signals. By preventing HER2 signaling, pertuzumab reduces proliferation and survival of these cancerous cells. Clinically, this provides an effective strategy in treating HER2-positive breast cancer.

    Inhibition of HER2 Dimerization

    Dimerization is crucial for HER2 function. Pertuzumab prevents HER2 from forming dimers with other related receptors, such as HER3. This inhibition is essential because dimerization activates pathways that promote tumor growth.

    Blocking this process disrupts signaling networks that would otherwise support cancer cell survival. The result is decreased cell division and increased apoptosis in tumor cells, enhancing therapeutic outcomes.

    Activation of Antibody-Dependent Cellular Cytotoxicity

    Pertuzumab also enhances immune response through antibody-dependent cellular cytotoxicity (ADCC). The binding of pertuzumab to HER2 helps recruit immune cells.

    These immune cells, such as natural killer (NK) cells, are activated to target and destroy HER2-expressing cancer cells. This mechanism provides an additional layer of antitumor activity, contributing to the effectiveness of pertuzumab in HER2-positive cancers.

    Trastuzumab with Pertuzumab

    The combination of trastuzumab and pertuzumab has become an important strategy in the treatment of HER2-positive breast cancer. This section explores how these two therapies work together to improve patient outcomes.

    Breast Cancer Treatment

    Trastuzumab, a monoclonal antibody, specifically targets the HER2 receptor, blocking signaling pathways that promote cancer cell growth. Pertuzumab also targets HER2 but binds to a different site, preventing receptor dimerization, which is essential for activating downstream signaling.

    When used together, these agents enhance therapeutic efficacy. Studies have shown that their combination leads to improved progression-free survival rates in patients with early-stage and metastatic HER2-positive breast cancer.

    This dual blockade not only targets the cancer more effectively but may also reduce the chances of resistance. The synergy between trastuzumab and pertuzumab represents a significant advancement in personalized cancer treatment, offering hope to many patients.

    Clinical Efficacy

    Pertuzumab has demonstrated significant clinical efficacy in the treatment of certain cancers, notably HER2-positive breast cancer. Its unique mechanism of action enhances the effectiveness of standard therapies. This section details relevant clinical trials, survival and response rates, and its comparison with other treatments.

    Relevant Clinical Trials

    Several key clinical trials have assessed the efficacy of pertuzumab in combination with trastuzumab and chemotherapy. The pivotal study, CLEOPATRA, involved over 800 patients and reported a significant improvement in progression-free survival (PFS). Patients receiving pertuzumab showed a median PFS of 18.5 months, compared to 12.4 months for those receiving the control regimen.

    Clinical Data

    Moreover, results from the APHINITY trial indicated a similar benefit in the adjuvant setting, where pertuzumab combined with trastuzumab increased the invasive disease-free survival compared to trastuzumab alone. These findings underline the drug’s role in improving outcomes for patients with HER2-positive breast cancer.

    Survival and Response Rates

    Pertuzumab has significantly enhanced survival rates among treated patients. In the CLEOPATRA trial, the addition of pertuzumab resulted in an overall survival rate of 86% at three years, compared to 84% for the control group. This difference highlights its impact on long-term outcomes.

    Response rates also reflect its efficacy. In the APHINITY trial, a notable 94.1% of patients exhibited a pathologic complete response when treated with both pertuzumab and trastuzumab preoperatively. These figures demonstrate its effectiveness in promoting favorable responses.

    Comparison to Other Treatments

    When compared to traditional therapies, pertuzumab shows improved efficacy in HER2-positive cancer management. For instance, the combination of pertuzumab and trastuzumab performs better than trastuzumab alone, resulting in improved PFS and overall survival rates.

    Other HER2-targeted therapies, such as lapatinib, provide different mechanisms but often have lower response rates. Studies have shown that patients on pertuzumab plus chemotherapy benefit from a robust treatment regimen, positioning it as a critical option in therapy for HER2-positive cancers.

    Future Directions in Research

    Research on pertuzumab continues to expand, focusing on ongoing clinical trials and exploring potential new therapeutic indications. These efforts aim to enhance understanding of its effectiveness and broaden its application.

    Ongoing Clinical Trials

    Numerous clinical trials are currently assessing the efficacy and safety of pertuzumab in various cancer types. One significant trial is investigating its use combined with trastuzumab and chemotherapy for HER2-positive breast cancer.

    Additional studies are exploring the sequencing of pertuzumab with other novel agents, such as immune checkpoint inhibitors, to evaluate potential synergistic effects. This research may offer insights into improved patient outcomes through combination therapies.

    Researchers are also examining different dosing regimens and administration methods to optimize treatment schedules. These trials aim to understand patient response based on specific biomarkers and genetic profiles.

    Potential New Indications

    Beyond breast cancer, there is growing interest in using pertuzumab for other malignancies. Investigations are underway to determine its effectiveness in gastroesophageal cancers, where HER2 overexpression is present.

    Researchers are also testing pertuzumab in combination with targeted therapies for lung and ovarian cancers. Exploring its role in these contexts may uncover new therapeutic avenues for patients who have limited options.

    Additionally, studies are exploring pertuzumab’s potential in neoadjuvant settings, where it could be used before surgery to shrink tumors. This could enhance surgical outcomes and improve long-term prognosis for patients.

  • Mechanism of Action of Nivolumab. Beating a Devil’s Advocate

    Mechanism of Action of Nivolumab. Beating a Devil’s Advocate

    Nivolumab helps your immune system fight cancers by blocking the tumor’s ability to evade the immune response.

    Nivolumab mechanism of action

    The main target of Nivolumab (brand name is Opdivo) is the Program Death protein (PD-1). Many immune cells have this receptor, the active form of which works as a brake for an immune response.

    Negative Checkpoint Proteins

    Imagine a cancer cell is put on trial. There is positive evidence that screams “guilty,” helping prosecutors cell to lay down a compelling case:

    1. Genetic mutations,
    2. Hijacked signaling pathways,
    3. Angiogenesis

    At the same time, there is always confusing evidence, perhaps even some that whispers “not guilty”—at least, not entirely.

    Negative checkpoint proteins comprised a latter group, and for tumor cells, they can play the role of “Devil’s advocate“, helping them to evade prosecution.

    PDL-1 and PD-1 complex is also called a negative immune checkpoint

    There are several types of negative checkpoint proteins, with PD-1 and CTLA-4 primary targets of novel anti-cancer drugs.

    Program Death Protein 1 (PD-1)

    The PD-1 receptor is a transmembrane protein comprising 288 amino acids. It is normally present on various immune cells, playing a huge role in the upregulation of an immune response:

    • B cells – the main type of antibody-producing cells;
    • T cells – part of the adaptive immune response, “elite forces” of your immune system, which receive training to recognise and eliminate bugs;
    • Natural killer (NK) cells usually represent the first line of defence.

    One particular subtype of T-cells, called Tumor-Infiltrating Lymphocytes (TIL), expresses abundant quantities of PD-1 receptors on their surface. TILs are responsible for finding and killing suspicious cancer-like cells in your body. This natural cancer monitoring tool is highly effective, cleaning around 20 cancer cells each day.

    How Does Cancer Immunity Work

    T-cell is a subtype of lymphocyte that can kill cancer cells by recognizing and binding particular receptors on the surface of a tumor cell

    The immune system works around the clock to find abnormal cells. TILs monitor billions of cells to check if they have any suspicious features – special proteins that might suggest these cells harbor some cancer traits and can potentially be a threat to the host.

    Imagine every second, TILs conduct a risk survey, analyzing both positive and negative evidence, before making a decision.

    If the evidence is overwhelmingly positive, the cells would be destroyed. One of those whistle-blowers is TCR (T-cell receptor), alerting the immune system of potential abnormalities such as cancerous major histocompatibility complex (MHC).

    On the other side of the scale is a PD-1, which works as a cell’s best advocate. In the case of melanoma, it is an advocate of the devil.

    By binding to the PD-1 receptor of cancer-killing cells, Nivolumab blocks one of the most important ways for tumor cells to escape the immune radar and evade the prosecution.

    Nivolumab, in nutshell is cancer anti-sparing medicine, helps immune system to be a tune for any suspects.

    Another prominent PD-1 inhibitor is Pembrolizumab, better known under the brand name Keytruda.

    PD-1 and cancer cells

    Cancers have a few tricks to slip from the radar of the immune system.

    Activating PD-1 is crucial for the survival of many cancers, like melanoma, renal cell carcinoma, astrocytoma, or colorectal cancer.

    To activate a “negative checkpoint,” they all express two types of Program Death Ligands – PD-L1 and PD-L2.

    PD-L1 are extremely aboundant on the surface of some types of melanoma and other solid tumors
    PD-L1 are extremely aboundant on the surface of some types of melanoma and other solid tumors

    Once the immune cell comes closer to inspect a the cancer one, the ligand PD-L1 would activate a PD-1, keeping tumor cells out of suspicion.

    PD-L1 in tumors

    According to the research, only one in three cancers express PD-L1. Particularly, some solid tumors are pretty good at producing the ligands on the surfaces of their cells:

    •  an ovarian cancer;
    • a melanoma;
    • a lung cancer.

    PD-L2 in tumors

    PD-L2, having a similar structure to PD-L1, creates a better and stronger bond with PD-1. Studies estimate the binding affinity of PD-L2 is two to sixfold higher.

    PD-L2 is found in many epithelial cancers and B-cell lymphomas.

    How does Nivolumab bind the PD-1?

    Paul Gauguin, a famous painter, once told his friend Bernard: “Do not copy nature. Art is an abstraction”. Although much of the art history of the 20th century proved it was worthy of advice, modern scientists still consider imitation to be one of the greatest tools in their arsenal.

    Nivolumab is a mere antibody. Our immune system produces billions of them each day to eliminate unwanted and harmful agents. A few things make Nivolumab special:

    1. It is monoclonal (mAb) – all copies of it have the same structure and represent the same class and a serotype of IgG.
    2. It is fully human – the structure is identical to a normal human antibody, which helps to stay longer in our bodies without eliciting our immune reaction.
    3. It belongs to the family of immune checkpoint inhibitors.
    4. It binds to a Program Death protein 1 with affinity and specificity. A single dose of nivolumab can link up to around 85% of all PD-1 receptors, and after 24 hours, around 70%.

    When Nivolumab connects to the PD-1 receptor on a T-cell or NK-cell it blocks PD-1’s ability to couple with PD-L1 or PD-L2, preventing a cancer cell from abusing this evasion route and getting off the immune radar.

    Nivolumab cancer demise

    What Cancers Can Nivolumab Treat?

    Nivolumab was developed by Bristol-Myers Squibb and received FDA approval in 2014, initially for treating metastatic melanoma.

    Over time, its applications expanded to cover multiple cancers:

    1. Melanoma

    Nivolumab was first approved for unresectable or metastatic melanoma. It demonstrated high efficacy, particularly in cases where other treatments failed.

    2. Non-Small Cell Lung Cancer (NSCLC)

    A significant milestone in the treatment of NSCLC, Nivolumab has shown effectiveness in patients with advanced or metastatic disease, especially after the failure of chemotherapy.

    3. Renal Cell Carcinoma (RCC)

    For advanced kidney cancers, Nivolumab improved overall survival rates compared to previously established treatments like everolimus.

    4. Head and Neck Squamous Cell Carcinoma (HNSCC)

    Nivolumab is particularly beneficial for recurrent or metastatic HNSCC with progression on or after platinum-based therapy.

    5. Classical Hodgkin Lymphoma (cHL)

    The ability of Nivolumab to respond to immune-evasive hematological cancers, such as cHL, has expanded its utility in hematological oncology.

    6. Colorectal Cancer (CRC)

    Certain CRC cases with mismatched repair deficiency (dMMR) respond well to Nivolumab due to high mutational burden, making the tumors more “visible” to the immune system.

    Nivolumab is an anticancer monoclonal antibody

    What Are the Side Effects of Nivolumab?

    Like all therapies, Nivolumab carries potential risks. Its immune system activation can lead to immune-related adverse events (irAEs), affecting both efficacy and tolerability. Below are some common and rare side effects:

    Common Side Effects:

    • Fatigue
    • Rash and skin reactions such as pruritus
    • Diarrhea or colitis
    • Musculoskeletal pain
    • General fever or flu-like symptoms

    Immune-Related Adverse Events (irAEs):

    These occur due to heightened immune activity and may involve any organ system. Examples include:

    • Lungs (Pneumonitis). If you are short on breath or have a persistent cough, please let your doctor know, as Nivolumab might increase the risks of your lung tissues being damaged.
    • Liver (Hepatitis): your doctor will check your liver function tests to ensure the enzymes are not elevated
    • Endocrine Disorders: Some normal endocrine cells express small quantities of PDL-1 and can be targeted by the immune system. Although recent studies haven’t found a link between PDL-1 expression and endocrine complications of nivolumab treatment, the doctor might check the levels of thyroid or pituitary hormones and request an ultrasound or MRI to check up on your glands.
    • Gut (Colitis): in rare cases, severe inflammation of the digestive tract may develop, prompting your doctor to check your stool for potential inflammatory signs or request a colonoscopy.

    While these side effects are typically manageable, it’s essential to let your doctor ASAP if you experience any problems and do your prescribed routine tests on time.