Monoclonal Antibodies: Magic Bullets of Modern Medicine

In this article you will learn what is antibody, what is the difference between monolocnal and polyclonal antibodies, how mAbs are classified and how they serve thousands of clinicians in treating cancer, autoimmune disorders, and rare diseases.

What is antibody

Immune system produce antibodies is to fight the foes of your bodies, or what your immune system recognizes as “an enemy”.

They are Y-shaped proteins, circulating in the blood or hummering around leucocytes, white blood cells, which work with them as a team to preserve integrety of your body.

Scientists discovered 5 major types of antibodies and called them immunoglobulins A, D, E, G, and M immunoglobulins (or shortly Ig). They all have different function, with dominant IgG representing 90% of antibodies circulating in the blood.

The unprecedented stability of IgG makes this class a a go to option for biotech companies for producing monoclonal antibodies.

How does an Antibody Work?

When an antibody binds a pathogen, it:

• Ensures the suspect won’t escape, by neutrilizing all its biological functions
• It calls for “reinforcement”, which might come in to ways:
  • NK-killer or a phagocyte comes to devour the pathogen (scientists call this opsonization)
  • Special forces called complement system can come, release enzymes that breaks integrity of the pahogen. The process is called Lysis.

How antibody became a medicine

Reaserches found a way how to grow them in lab using the “Hybridoma technique”. Hybridoma is a crossbreed of two lines of cells:

• First parent cell gives it immortality
• Second gives it values – ability to produce “pure” single line of antibodies, monoclonal, as scientists called them.

Scientists use different methods to identify, distill, and make them more stable, before it would be considered as a medicine.

Polyclonal versus Monoclonal antibodies

Monoclonal means antibodies are produced by single line (clone) cells using a single boilerplare, so all of the antibodies are identical.

Prefix poly- means many, so polyclonal antibodies are different in structure and targets.

Types of Monoclonal Antibodies

First hybridomas were grown in a mice and we fully murine. The first antibody has seen the market is Muromonab. Notice it has “mo” suffix, literally meaning “mouse” mAb.

Unfortunatelly, mouse mAbs are not ideal as a medicine. Their buildup is too “foreign”for our immune system, thus fast immune response from the body ensues the injection.

Scientists soon found a solution, a transgenic mouse, that produces three quoters of fully human antibody. Less immune reaction, more stay in the blood – more therapeutic efficacy. Infleximab and Rituximab (Rituxan) are two most famous examples of this type, aslo known as chimeric. Xi is for chimeric.

Next generation is humanized, where only six slices (CBRs) of murine antibodies left. The example is an anti-cancer antibody Trastuzumab (Herceptin) and Pembrolizumab (Keytruda). Substem -zu is for huminized.

Can you guess the next generation? If you think “human”, you are righ. A purely human antibody with minimum immunegenicity – ability to attract attention and elicit an immune response.

Full classification of mAbs

• Murine: Fully derived from mice. They can trigger strong immune responses but may be less effective in humans.
• Chimeric: one quoter – a mouse and and three quoters – a human. They are more familiar to immune our immune system, so lesser chance to develop immune response and be eliminated prematurely – before commencing good deads in the body as a medicine.
• Humanized: predominantly human, with only a small bits are from mice. There is a better complience with a human immune system and less chance to get cough and eliminated.
• Fully Human: having entirely a structure, identical to human conterpart. The risk of an immune rejection is minimal.

Monoclonal Antibody – What Happens After Injection

Mechanisms of Monoclonal antibodies do not differ from a way natural antibodies work:

• Binding. First, monoclonal antibody binds to the specific antigen. When the antibody connects to its target, it forms a stable complex. This specificity helps ensure that the treatment focuses only on the harmful cells, limiting damage to healthy cells. This targeted binding is a critical step in the therapeutic process.
• Inactivation. Once mAb attaches to the target, the antigen became no longer active. At this step, viruses lose their ability to invide healthy cells, bacteria – release their enzymes to target our tissues and organs, some immune componds, like interleukins – to send signals promoting inflammation.
• Immune System Modulation. At this stage, antibody calls for support, by signalling to the immune team to step in and get rid of the unwanted agent. It can go two ways:
  • Phagocyte or an NK-killer will devour the antigen
  • Compliement system will release chemicals to break down a bug into pieces.
  • Finally, antibodies can contain effects of “toxins” by signalling to phagosite to gulp them down.

The processes discribed above are ovesimplification of the real world picture. The real intricacies of the immune response and role of antibodies are way beyond the scope of the this article.

It worth to mention some monoclonal antibodies are designed to ease the immune reaction and calm inflammation. Some of them might send negative signals to “immune team” and prevent opsonisation or lysis of the cells, specifically when immune response “goes bonkers” and attacks its normal organs.

Therapeutic Use of Antibodies

Monoclonal antibodies have many therapeutic applications. They are widely used in treating cancers, autoimmune diseases, and infections. Some common uses include:

• Cancer Treatment: mAbs can target cancer cells pouning upon tumor’s key survival strategies:
  • Excape from immune system
  • Agressive reproduction
  • Stealing the resources away from normal cells and organs
• Autoimmune Diseases. Automimmune means our own defence system is taking upon our own organs and tissues. mAbs help to calm this agression by blocking specific pathways in diseases like rheumatoid arthritis, lupus, psoriasis, reducing inflammation and symptoms.
• Infectious Diseases: Some mAbs can neutralize viruses or bacteria, providing targeted treatment to patients.

Monoclonal Antibodies in Cancer Treatment

Monoclonal antibodies are bridging the existing gap in cancer treatment, providing more and more targeted options and shifting the paradigm

from:

“Let’s just poison the whole body in a calculated move that cancer might be more affected than normal organs and tissues”.

to:

“Let’s try to snipe cancer cells minimizing impact on rest of the body”

Negative Checkpoint Inhibitors

Checkpoint inhibitors are a type of monoclonal antibody that help the immune system recognize and attack cancer cells.

Remember the math: “Minus and minus gives plus“. This is exact logic of Negative Checkpoint inhibitors:

• Negative checkpoints, when activated, calm down immune response and help some cancer to evade.
• Antibodies target Negative checkpoints, enhancing anti-cancer immunity.

Program Death Receptor (PD-1) inhibitors:

• Nivolumab (Opdivo) works by blocking the PD-1 protein on T cells. This action boosts your immune response against cancer.
• Pembrolizumab (Keytruda) also targets PD-1, enhancing the ability of your immune system to attack tumors.

Program Death Ligant (PD-L1) inhibitors:

• Atezolizumab (Tecentriq and Tecentriq Hybreza)
• Avelumab (Bavencio)
• Durvalumab (Imfinzi)

These therapies can be used in various cancers, including melanoma, lung cancer, and kidney cancer. With checkpoint inhibitors, many patients have experienced better outcomes and longer survival rates.

Cancer Cell Apoptosis

Monoclonal antibodies can also induce apoptosis, which is a process that leads to programmed cell death in cancer cells.

Examples include:

• Rituximab targets CD20 on B-cell non-Hodgkin lymphoma. This binding triggers apoptosis in cancerous B cells.
• Trastuzumab (Herceptin) focuses on HER2-positive breast cancer, leading to targeted destruction of those cells.

This approach can make treatments more effective and reduce the chance of the cancer spreading. Monoclonal antibodies continue to offer new options for patients fighting cancer, significantly impacting survival and quality of life.

Monoclonal Antibodies in Immune Response

Immune system works around the clock to remove harmful or unwanted agents from your bodies.

Mistakes can happen, and some times immune system attacks your own organs and tissues, producing billions of antibodies to kill your cells. These type of mistakes can hapen in a form of sporadic “autoimmune reaction“. Sometimes a person can get chronically ill and more sustained immune response develops against mormal tissues and organs, then we call it an “autoimmune disease“. The prime example is rhematoid arthritis or lupus.

Interleukin Inhibition

Interleukins are proteins that help regulate immune responses. Some monoclonal antibodies work by inhibiting specific interleukins. For example, anti-IL-6 antibodies can block the action of interleukin-6, which is involved in inflammation.

By blocking these interleukins, monoclonal antibodies can reduce excessive immune responses. This approach is useful in treating autoimmune diseases, where the body attacks its own tissues. Reducing inflammation can alleviate symptoms and improve your quality of life.

Advantages and Challenges

Monoclonal antibodies offer significant benefits in treating various diseases, especially in immunotherapy. However, there are also challenges related to resistance and side effects that can impact their effectiveness.

Efficacy and Precision

Monoclonal antibodies are designed to target specific antigens on cells. This precision allows them to attack diseased cells while sparing healthy ones.

Key Benefits:

• High specificity: They bind only to their target, reducing damage to normal tissues.
• Strong efficacy: Many treatments show promising results in cancer and autoimmune diseases.
• Combination therapy: They often work well with other treatments, enhancing overall effectiveness.

This targeted approach can lead to improved outcomes for patients compared to traditional therapies.

Resistance and Side Effects

Despite their benefits, monoclonal antibodies face challenges such as resistance and side effects. Some tumors can adapt, making treatments less effective over time.

Common Issues:

• Resistance: Cancer cells may change their surface markers, making them unrecognizable to the antibody.
• Side effects: Common side effects include fever, chills, and allergic reactions. Some patients experience more serious issues like infusion-related reactions.

These challenges can affect treatment plans and require careful monitoring by healthcare providers.

Future Directions in mAb Therapy

More than 200 therapeutic mAbs are available for clinicians to date. With more than 1400 candidates are being investigated the future is looking bright for mAbs.

Innovations in Design

New designs of monoclonal antibodies are changing treatment approaches. Scientists are exploring biologics that better target specific cells or pathways. This precision can reduce side effects while improving efficacy.

Receptor constructs are another innovation. These are designed to activate or block specific pathways in your body. This targeted action can lead to more effective therapies against cancers or autoimmune diseases. For example, modified antibodies with dual functions can attack cancer cells while also stimulating the immune system.

These innovations will likely increase the range of diseases treatable with mAbs. They help create more personalized medicine tailored to individual patients’ needs.

Combination Therapies

Combination therapies are gaining attention in mAb treatment. By pairing monoclonal antibodies with other treatments, such as chemotherapy or immunotherapy, you can enhance their effectiveness.

For instance, using mAb therapy alongside traditional treatments may improve patient outcomes. This approach can help overcome resistance that some cancers develop. The right combinations can also help target multiple pathways at once, increasing the chance of successful treatment.

Furthermore, combining mAbs with other biologics can lead to synergistic effects. These combinations can be particularly beneficial in treating complex diseases, where multiple mechanisms contribute to disease progression. This strategy can pave the way for more robust treatment plans.

Key Takeaways

• Your immune system makes antibodies to fight bugs.
• In 1975, scientists designed a “hybridoma”, a first “factory for antibodies”. Then researches found way how to streamline the production, purify, stabilize it, and the first “therapeutic monoclonal antibodies” started seeing the market.
• Antibodies have a single specific target, usually it is a protein, that was recognised by the immune system as foe. Sometimes your immune system might attack your own organs and tissues, what we call “autoiimune reaction” or if it is a chronic condition, it is called “autoimmune disease”.
• First Monoclonal antibodies were designed to calm “autoimmune reactions“, such as “Graft versus host disease”, when immune system attacks a transplanted organ, seeing it as an enemy. It was muromonab-CD3.
• Next generation of mAbs has expanded their application to cancers and chronic autoimmune disease, such as reumathoid arthritis, systemic lupus erythematous, psoriars and dozen others.
• The area of therapeutic mAbs is developing rapidly bringing more tools and opportunities for doctors and patients.