Bispecific Antibody Toxicity

What is Bispecific Antibody Toxicity?

Bispecific antibodies (or bsAbs) are very exciting in the world of medicine right now. They’re designed to fight against two different harmful substances at the same time. Here’s a picture showing how Blinatumomab, one of the bsAbs, works. Because these unique antibodies can latch onto two different targets (known as epitopes), they can work against a variety of diseases, such as cancer, autoimmune diseases, and infections.

The US Food and Drug Administration (FDA) has given the green light to a few bsAbs so far:

• Blinatumomab, approved in 2014, is used against CD19-positive B-cell precursor acute lymphoblastic leukemia. It helps fight against a type of cancer that starts from the white blood cells in the bone marrow.
• Emicizumab, from 2017, reduces how often bleeding occurs in people with Hemophilia A, a genetic disorder that prevents blood from clotting properly, who have inhibitors against factor VIII.
• In 2021, Amivantamab was approved for use in treating a certain type of non–small cell lung cancer.
• Faricimab, from 2022, is used to treat conditions that affect the back of the eye, including a type of age-related macular degeneration (which affects central vision) and diabetic macular edema (a complication of diabetes).
• Other medicines, like Teclistamab and Mosunetuzumab were approved in 2022 for the treatment of certain types of cancer.
• Also, Epcoritamab, Glofitamab, Talquetamab, and Elranatamab are in the process of getting approved for the treatment of a type of cancer called large B-cell lymphoma and a specific type of multiple myeloma.

Although these bsAbs are very promising in treating diseases, they can also cause some side effects. Some of these side effects, like cytopenias (low blood cell count), diarrhea, changes in liver function test and a fast breakdown of cancer cells that can cause kidney damage (tumor lysis syndrome), are similar to those seen with conventional chemotherapy. Unique side effects to these medications include a condition where high amounts of immune substances are released into the bloodstream (Cytokine release syndrome), nervous system-related issues and a sudden increase in symptoms of certain types of cancer (tumor flare).

What Causes Bispecific Antibody Toxicity?

The human body naturally produces antibodies – proteins that recognize and fight off invaders like infections or cancer. These naturally produced antibodies usually target one thing at a time. However, scientists have found a way to create special, made-in-the-lab antibodies that can target two different things at once. These are called bispecific antibodies (bsAbs).

Bispecific antibodies work by binding to two different areas on the cells at the same time: one on immune cells (your body’s defense system), and one on tumor cells (the bad guys). This dual action kick-starts your immune system into action, attacking and destroying the tumor cells.

The destruction of tumor cells involves a process called antibody-dependent cellular cytotoxicity, where special components like perforins and granzymes are released to kill the tumor cells. At the same time, inflammation causing substances like interleukin-2 (IL-2), IL-6, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) increase in the area around the tumor.

But, like many cancer therapies, bsAbs can have side effects. The substances released can also cause overall inflammation in the body. The five major side effects associated with bsAbs can include infections, on-target off-tumor toxicities (effects on non-cancer cells), cytokine release syndrome (CRS, a rapid immune response leading to fever and fatigue), immune effector cell-associated neurotoxicity syndrome (ICANS, nervous system side effects), and tumor lysis syndrome (TLS, a rapid release of cellular contents resulting in electrolyte imbalance).

Risk Factors and Frequency for Bispecific Antibody Toxicity

Understanding the potential risks of bispecific antibody (bsAb) treatments mainly comes from clinical trials. Real-world information is not widely available yet. These trials show that patients can experience some negative effects, known as toxicity.

• Between 38% and 76% of patients developed infections.
• Severe (grade 3) infections occurred in 14% to 44% of patients.
• Cytokine release syndrome (CRS) happened to 27% to 59% of people, but only 1% to 3.5% had severe CRS.
• Neurological side effects or immune effector cell-associated neurotoxicity syndrome (ICANS) were noticed in 10% to 65% of treated patients. Out of these, 10% to 15% experienced severe effects.
• The rate of tumors lysis syndrome (TLS), which is a serious complication, mainly depends on the type of cancer being treated and is usually lower than for traditional chemotherapy.

Signs and Symptoms of Bispecific Antibody Toxicity

Patients undergoing treatment with bsAbs, a type of biological drug, may encounter toxicity issues. The type of symptoms vary, but can get harmful, especially with individuals who are experiencing cardiorespiratory arrest. Immediate life-saving measures need to be undertaken in these cases. After the patient is stable, a more thorough examination can be pursued.

Common reactions related to the infusion of these drugs include fevers, chills, and signs of allergies. It’s important to monitor for these and to carefully check any fevers for potential infection connections. There’s also a risk of opportunistic infections like Epstein-Barr virus, cytomegalovirus, adenovirus, herpes simplex virus, hepatitis B or C, pneumocystis jirovecii, toxoplasma, and aspergillosis. Other potential side effects include diarrhea, skin rashes, nail disorders, loss of taste, and liver inflammation.

A condition called CRS can develop, presenting with symptoms ranging from mild flu-like feelings to severe life-threatening diseases. Severity is split into five grades: mild fever and symptoms (Grade 1), to serious, life-threatening conditions requiring urgent intervention (Grade 4), and in the worst case, death (Grade 5).

Another important consideration is ICANS, which can occur either with CRS or on its own. Symptoms can include headache, confusion, hallucinations, tremors, abnormal gait, speech issues, behavioral changes, visual or auditory hallucinations, motor impairment, seizures, swellings in the brain, and even death. As for TLS, it can lead to high levels of uric acid, potassium and phosphate in the blood, kidney failure, and heart rhythm issues.

• Fever and chills
• Allergy symptoms
• Risk of various infections
• Diarrhea
• Skin rash
• Nail disorders
• Loss of taste
• Liver inflammation

If any new symptoms appear in a patient receiving bsAb treatment, they should be evaluated immediately for serious side effects. Information about the specific disease, stage of cancer, bsAb type being used, how long the bsAb treatment has been in progress, and details of any fever should all be collected. A careful physical check-up should be performed, which includes assessing vital signs, oxygen saturation, chest sounds, abdominal issues, and nerve system functioning. Frequent nerve system exams can help identify any minor changes compared to the usual baseline condition.

Testing for Bispecific Antibody Toxicity

In the process of evaluating potential harmful effects from bispecific antibodies (bsAb) treatment, which is a type of targeted cancer therapy, several steps are followed. The results obtained can give doctors useful information about how severe any side effects might be and help them make decisions about how to manage these side effects.

Inpatient Monitoring

If you’re starting bsAb therapy, it’s generally recommended you stay in the hospital to be closely watched during the first few days of therapy. Just how long you stay in the hospital will depend on the type of bsAb being used, the specific guidelines related to that product, and the recommendation of your doctor. In some cases, the dosage of the antibody is increased slowly, and doctors usually like to closely watch patients for a day or two after this process is over.

Laboratory Testing

Several laboratory tests are usually ordered. These include a blood count, a full metabolic panel, tests for uric acid and lactate dehydrogenase (both measure how well your cells are working), tests to see how well your blood clots, and tests to check for bacteria in your blood, urine or respiratory system. These tests can reveal important information. For example, low counts of neutrophils (a type of white blood cell) can suggest you don’t have enough white blood cells. Increases in certain chemicals, like creatinine, uric acid, and lactate dehydrogenase, and changes in electrolytes (like salt levels) can suggest a condition called tumor lysis syndrome, which can occur when a large number of cancer cells are killed very quickly.

Imaging

Imaging can be used to provide additional information about your condition. Chest x-rays can check for lung conditions, like pneumonia, or other complications related to the bsAb treatment. If you’re in the hospital and suddenly have trouble breathing, ultrasound can check for blood clots. A type of ultrasound called an echocardiogram can check for heart problems. If you’re having symptoms that suggest problems with your brain or nerves, a CT scan or MRI can help. These can take detailed pictures of your brain to check for stroke, bleeding, or other issues. However, MRI can take longer and isn’t right for everyone – for example, if you can’t keep still for long or have certain types of metal implants.

Physiologic Tests

An electrocardiogram, which measures the electrical activity of the heart, can be done if your doctor thinks the bsAb might be affecting your heart, or if you’re having chest pain or trouble breathing. If you’re having seizures or other symptoms that suggest a problem with the brain, an EEG might be done. This test measures the electrical signals in your brain.

Some tests may involve invasive procedures. For instance, a lumbar puncture (or spinal tap) might sometimes be needed. But usually, this is only after imaging has been used to check for swelling in the brain.

Inflammatory Markers

Lastly, tests might be done to measure certain chemicals in your blood that can show if there is inflammation happening. While the diagnosis of conditions related to the bsAb are typically made based on symptoms and physical exam findings, these tests can lend support to the diagnosis. Higher levels of these chemicals often suggest more severe side effects.

Treatment Options for Bispecific Antibody Toxicity

It’s critical to promptly identify and manage bsAb toxicity in order to avoid lasting damage to vital organs and potential death. Treatment depends on the specific effects and how the patient presents their symptoms. Two general strategies include supportive care and immune system regulation.

Supportive Care involves the use of fever-reducing medications for fevers, fluids with or without other medications for low blood pressure, and mechanical ventilation for breathing support if necessary. It’s key to begin treatment with broad-spectrum antibiotics as quickly as possible if there’s an ongoing risk of infection.

In case of serious immune-related side effects like CRS or ICANS, Immunosuppressive therapies, which weaken the immune system response, should be considered. Rating the severity of these side effects can guide doctors in starting the right treatment. Less severe CRS can be managed with fluids, antihistamines (medications used to treat allergies), and fever-reducing medications. Patients experiencing severe CRS should be closely monitored and treated in the intensive care unit.

If CRS reaches severity levels from 3 to 4, a steroid named dexamethasone is recommended, which can be given through the mouth or inserted directly into the veins. Ideally, this is done every 8 hours for 3 days and then slowly reduced over 4 days. If this treatment isn’t effective, then a dose of tocilizumab, a medication that blocks a substance in the body that triggers severe inflammation, is given intravenously. Tocilizumab has shown positive results in severe CRS.

For ICANS of grade 2 or higher, dexamethasone treatment is advised, which is then gradually lowered over the next 2 to 5 days. Anti-seizure prevention with levetiracetam is recommended for patients who have ICANS and are at high risk of experiencing seizures. If seizures do occur, the doses of these anti-seizure medications should be increased. While early use of steroids is the standard practice, patients with ICANS do not require tocilizumab unless they also have CRS, according to the Mayo Stratification for Myeloma And Risk-Adapted Therapy guidelines.

Depending on how severe the toxicity is, it may be necessary to stop bsAb treatment temporarily or permanently, or to adjust the dose. Treatment may need to be paused for grade 3 toxicity, or permanently stopped if it reaches grade 4.

Getting help from specialists in areas like neurology (nervous system), pulmonology (respiratory system), and infectious disease can be beneficial in handling difficult cases. This approach helps ensure that the patient gets a well-rounded treatment.

TLS, a condition that can also occur due to bsAb toxicity, is managed in a similar way to other causes. Should patients show high tumor levels or uric acid levels prior to treatment, they should be started on fluids and a medication called allopurinol to prevent this. If TLS develops after starting bsAb treatment, allopurinol is given every 8 hours. If the patient has kidney issues, Rasburicase may be added to the treatment. Regular testing of kidney function and uric acid levels is recommended and doctors that specialize in the kidneys should be consulted if necessary.

What else can Bispecific Antibody Toxicity be?

The symptoms of bsAb toxicity can sometimes look like other medical conditions. This can make it hard to diagnose, as doctors need to rule out the following conditions:

• Tumor Progression: Some symptoms of bsAb toxicity can look like the worsening of a tumor. For example, symptoms that affect the nervous system, like those of brain metastasis. Or, trouble breathing or coughing could be seen as a sign of lung involvement getting worse rather than lung damage from bsAb toxicity.
• Infections and Sepsis: Some symptoms can seem like severe infections or sepsis. The doctor might need to consider things like pneumonia (both viral and bacterial), a urinary tract infection, or hepatitis.
• Cardiovascular Complications: Because most bsAbs are used as third or fourth treatments, patients might have already been given other treatments that can harm the heart. Heart problems, irregular heart rhythms, and heart attacks might be confused with bsAb toxicity. Specific tests can help tell these conditions apart.
• Venous Thromboembolism: People with cancer are at greater risk for clotting in the veins. Symptoms like swelling in the legs, shortness of breath, chest pain, and changes in blood pressure could signal this issue. The care team should be on high alert for this and might need to order imaging tests to check for this possibility.
• Hemophagocytic Lymphohistiocytosis: This is a serious condition where the body’s immune system goes into overdrive. It can seem like another immune activation problem called CRS. Specific tests and markers can help tell these two apart.
• Cerebrovascular Conditions: Conditions like strokes and a condition called metabolic encephalopathy might all be mistaken for ICANS (a problem caused by bsAb). A brain MRI can help to find the cause of the symptoms.

This underscores the importance of careful clinical evaluation and to always keep bsAb toxicity in mind when looking at potential diagnoses to ensure the right treatment is provided.

What to expect with Bispecific Antibody Toxicity

The outlook for patients experiencing toxicity from bsAb (short for bispecific antibodies, a type of medication that can bind to two different types of proteins at the same time) depends on many factors. These include how severe the toxicity is, how quickly treatment is given, and the individual patient’s health specifics.

If detected early and managed properly, many bsAb-related side effects can be effectively controlled. This allows patients to keep benefiting from these novel treatments. However, if these side effects are severe or not treated, they can have negative impacts. In some instances, they may even require stopping the bsAb treatment.

Possible Complications When Diagnosed with Bispecific Antibody Toxicity

Side effects related to the toxicity of bispecific antibody (bsAb) therapies can vary and may include the following:

• Secondary infections: The use of treatments to suppress the immune system and control the toxicity can increase the likelihood of getting other infections.
• Organ damage: If the toxicity from the bsAb therapy is prolonged or severe, it may harm vital organs like the liver or kidneys.
• Treatment cessation: In some situations, the toxicity might require stopping the bsAb therapy. This could limit the available treatments for the underlying disease.

This highlights why it’s crucial to closely monitor patients, intervene quickly if problems arise, and properly weigh the risks when using bsAb therapies, to ensure that they are safe and effective.

Preventing Bispecific Antibody Toxicity

Teaching patients about their health is crucial in avoiding and dealing with side effects from bsAb (Bispecific Antibodies) treatments. Here are the suggested steps:

• Understanding your treatment: Patients should know all the details about the bsAb treatment they’re having, the possible side effects, and why it’s crucial to promptly let their doctor know about any unusual symptoms.
• Sticking with the treatment plan: To get the best results, patients should continue to follow their doctor’s instructions, including taking their medicine as scheduled and attending all check-up appointments.
• Recognising symptoms: Patients should be taught how to spot early signs of side effects and know when it’s necessary to seek instant medical help.
• Storing medication: Patients should be told how to correctly store their medication to ensure that it remains effective, when necessary.

Together, these steps highlight how crucial it is for patients to understand their treatments for improving the results of bsAb therapy and looking after their overall health.