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The Commercialization Process for Antibody Therapeutics

The development of new, safe, and effective drugs for diseases such as cancer, infectious diseases, and autoimmune disorders is a multi-billion-dollar industry worldwide. Since their initial approval in the 1980s, antibody therapeutics have emerged as the predominant class of new drugs for treating these diseases and improving patient outcomes.

Antibody therapeutics are ideal candidates for treating these difficult-to-treat diseases as they are highly specific and consequently, new antibody therapeutics have less side-effects than traditional, non-specific therapeutic drugs. The rapid and dramatic evolution in antibody engineering since the 1980s has made this possible. The global market for these drugs is projected to be worth $300 bn by 2025.

However, the commercialization process for this class of drugs is highly complex. Like all new drugs entering the market, antibody therapeutics undergo a long and expensive development process from discovery and preclinical development, through clinical trials and regulatory approval, to manufacturing, scale-up, market launch, and post-market monitoring. This article will explore this complex but important process.

Monoclonal Antibodies versus Polyclonal Antibodies

Discovery and Preclinical Development

This stage of the commercialization process is the first step toward developing a new antibody therapy for a disease such as cancer or autoimmune conditions. This starts with target identification. Specific biological targets such as cancer markers and viral proteins, which antibodies work on to fight disease, are identified before they enter the preclinical trial phase. 

Preclinical trials are an essential part of the drug discovery and development process. Before a new antibody therapy is approved for clinical trials on humans, it must go through a series of laboratory studies on animal models and other models to ensure it is safe. Additionally, this stage assesses the drug’s biological activity.²

Preclinical development of an antibody therapeutic, like all drugs, involves several methods and studies such as in vivo and in vitro assays. Data on toxicity, dosage, pharmacokinetics, and potential side-effects are generated during these studies, which inform more complex clinical trials on humans. 

Antibody therapies are a unique class of drugs due to high specificity and affinity for a binding partner, requiring specific antibody engineering methods during the drug discovery and preclinical stages.

Several methods are used in antibody engineering to create high-affinity and specific antibodies such as monoclonal and bi-specific antibody therapies. These include homology modeling, protein-protein docking, in vitro affinity maturation, 3dMAbDesign, recombinant DNA technologies to tailor antibody properties, and protein interface prediction. 

Trends in the early-stage clinical development of antibody therapeuticsPlay

Clinical Trials and Regulatory Approval

Clinical trials involve testing new drugs and therapies on various human cohorts to evaluate their efficaciousness, safety, side-effects, proper dosage, and obtain data which is used for regulatory approval. Antibody therapeutics go through the same clinical trial stages as all other drugs. 

Phase I trials involve testing in healthy volunteers or small patient groups to evaluate safety and proper dosage. Phase II trials test the drug on larger patient populations side-effects and efficacy. Phase III trials are large-scale trials. This final trial confirms the drug’s efficacy, monitors side effects, and compares a new drug with existing treatments on the market. This can be a long, complex, and expensive process.

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The regulatory process is vital to ensure that new drugs such as antibody therapeutics are safe for patients and can effectively treat the diseases they are designed to combat. The regulatory approval process was not designed for speed, although the COVID-19 pandemic demonstrated that regulatory approval can be sped up given the right resources. 

Agencies such as the FDA and EMA are involved in the regulatory process and there are some specific applications new drug sponsors need to file for regulatory approval. The Investigational New Drug (IND) Application, for instance, is filed during the preclinical stage, and is used by the FDA to ensure that the drug will be safe for humans in clinical trials. 

The regulatory process can take a long time, potentially over a decade before a new drug is released to the market. As antibody therapeutics are an emerging class of drug, the regulatory process is especially important and presents several challenges for pharma companies and organizations developing them for the treatment of diseases.

Manufacturing and Scale-Up

Once the trial process is complete and regulatory approval has been granted, an antibody therapeutic can enter the manufacturing stage ready to be commercially launched. There are some unique challenges associated with the manufacturing and scaling-up of this class of drugs that mark their differences to other types of drugs on the market. 

Firstly, bioreactors and cell cultures are necessary to produce antibodies at scale. This can be an expensive and complex procedure. Secondly, rigorous testing is vital for quality control and ensuring consistent purity and efficacy. Moreover, cost-effective, reliable supply chains are needed for large-scale distribution.

Biologics and Biosimilars: A New Frontier in Therapeutics

Market Launch and Post-Market Monitoring

These are the final commercialization steps. To successfully launch a new pharmaceutical product such as an antibody therapeutic, there must be strategies in place to ensure patient access, proper pricing, and in the case of markets such as the US, insurance coverage. 

Post-marketing surveillance is equally important as a new or emerging drug such as an antibody therapeutic must be monitored to ensure its long-term safety and efficacy. This is essential and is often required by regulatory bodies. Some problems and side-effects may not have been found in the clinical trial process, necessitating constant long-term monitoring. 

Patient and physician education on new therapeutics, especially ones which have been designed to treat underserved medical conditions or may be an emerging class of therapeutics, is essential as it impacts the safe and efficacious use of a drug such as an antibody therapeutic. 

Challenges and Future Outlook

As can be seen above, the commercialization process for antibody therapeutics is long, complex, and can be fraught with challenges at every stage, from target identification through post-market surveillance.

Some specific challenges for this emerging class of therapies are high R&D costs, regulatory hurdles due to their status as new and emerging therapies, and competitive market pressures. 

Additionally, if the therapy is being developed to fight a condition such as an autoimmune disease that only affects a small patient population, finance and sponsorship may be difficult as it may not be seen as financially viable.Despite the challenges of commercializing these therapeutic drugs, there are some key trends that are shaping the future of their development. These include personalized antibody therapies and personalized medicine, biosimilars (drugs that contain active substances from a biological source) and antibody-drug conjugates, which deliver cancer-killing therapies without damaging normal, healthy cells. 

In summary, antibody therapeutics are an emerging, powerful, and highly specific class of drugs that are seeing intense research focus currently for their ability to target cancers, autoimmune diseases, and other debilitating conditions safer and more effectively than conventional therapies. They represent one of the most exciting frontiers in medical science now.

References

1. Lu, R-M et al. (2020) Development of therapeutic antibodies for the treatment of disease Journal of Biomedical Science 27, article no.: 1 [online] BMC. Available at: https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0592-z (Accessed on 09 November 2024) 

Referencee AZoLife Sciences.

Psychedelics: A new hope for substance abuse treatment

Study: From Research to Reality: Crafting an Image of the Current State of Psychedelic-Assisted Psychotherapies for Substance Use Disorders. Image Credit: YARPhotographer / Shutterstock.com

How can modern psychedelic research and traditional approaches integrate to address substance use disorders and mental health challenges?

A recent study published in the Journal of Studies on Alcohol and Drugs discusses the history and current state of psychedelic research for the treatment of substance abuse disorders (SUDs).

Psychedelics

Psychedelics are consciousness-altering drugs, some of which include lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), psilocybin, and mescaline. Methylenedioxymethamphetamine (MDMA) and ketamine are also considered psychedelics; however, these drugs have different mechanisms of action. 

Although psychedelics have been exploited for centuries to induce altered states of consciousness, their use, as opposed to their abuse, has largely been unexplored in modern medicine. In fact, several studies have indicated the potential utility of psychedelics for individuals who have mental illness due to traumatic experiences, false beliefs, and unhealthy behavioral patterns, such as posttraumatic stress disorder (PTSD) and depression. 

The recent coronavirus disease 2019 (COVID-19) pandemic led to global changes in the use of methamphetamine, alcohol, and cannabis, as well as a significant increase in opioid overdoses in the United States. Thus, another promising application of psychedelics is their potential use for treating SUDs. 

However, restrictive policies, poor funding, lack of equitable and diverse recruitment and access, as well as the multiplicity of small-scale psychedelic research programs have prevented researchers from effectively investigating the effects of psychedelics in the treatment of SUDs.

Overview

Over the past seven decades, researchers have become increasingly interested in examining the potential use of psychedelics in traditional medicine. Despite federal policies banning recreational drug use, researchers have elucidated some of the biological effects of psychedelics on the central nervous system (CNS) and their potential role in the treatment of SUDs. Nevertheless, there remains a lack of well-controlled multi-center trials and systematic reviews in this area. 

As researchers continue to examine the pharmacological potential of these drugs, it is crucial to address their addiction and abuse potential, the legalization of recreational drugs, and the attempts of pharmaceutical companies to introduce high-selling psychedelics as therapies for mental illness. 

History and current use of psychedelics

Psychedelics like ayahuasca, Peyote, and psilocybin-containing mushrooms have been used throughout history by traditional healers and indigenous communities for both spiritual and health purposes. By recognizing these contributions, researchers can benefit from the potential benefits of traditional usage patterns while investigating the use of these drugs for treating SUDs and other mental health disorders. 

For example, a hybridized SUD therapy program in Peru utilizes ayahuasca to treat alcohol and drug use. At one year following treatment, reduced depression and anxiety, higher quality of life, and reduced severity of addiction have been reported.

One notable contribution is the acknowledgment that key experiences of treatment participants might provide more insight than the search for putative “active ingredients” of interventions as complex as psychedelic-assisted treatment.”

Purging in psychedelic treatment

Psychedelic use, specifically ayahuasca use, is closely linked to vomiting as a means of purging the body. This is reported to have spiritual, Amazonian, and clinical benefits. 

These spiritual benefits are linked to Christian mystical experience and the Amazonian goals of restoring the internal balance of the individual, whereas clinical benefits are reflected in terms of improved wellness measures. Rather than being a negative effect of ayahuasca use, purging may be an integral part of its healing effects in some situations. 

Conclusions

The optimal approach to psychedelic-assisted treatment involves mutual respect for and recognition of the value of both traditional and modern applications. Thus, mixed-methods research is crucial, as traditional approaches may help identify a better therapeutic agent or program than traditional approaches to identifying and isolating active ingredients. 

However, it is essential to evaluate and quantify the success rates of traditional approaches to psychedelic use, as well as elucidate the biological mechanisms that may contribute to their therapeutic effects. Researchers must recognize and credit traditional history and practices throughout these efforts to protect these cultures from being exploited, ignored, and suppressed by pharmaceutical industries.

The rush to patent processes in psychedelic treatments of addiction and other psychiatric conditions reflects the enormous greed of private commercial entities to benefit financially from vulnerable patients in need of effective therapies.

Thus, regulatory control of psychedelic therapies is vital to establish rigorous research standards that can lead to the generation of sufficient evidence in this area. Without this type of overview, private corporate interests may seek to exploit governmental support for crucial research needed to address these mental health issues.

Journal reference:

Mast cells found to capture and employ neutrophils during allergic reactions

Known for their role in allergic reactions, mast cells have long been recognised as key players in our immune system. When they encounter allergens, they release chemicals that trigger typical allergy symptoms such as tissue swelling and inflammation. Now, researchers at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the University of Münster have discovered a hidden talent of mast cells: they can capture and use another type of immune cell called neutrophils. This surprising discovery sheds new light on how our immune system works, particularly during allergic reactions.

Inflammation is the body's response to harmful stimuli, characterized by heat, pain, redness, swelling, and loss of tissue function. When balanced, inflammation protects the body by clearing harmful agents and initiating tissue repair. However, excessive inflammation can cause tissue destruction and disease. Key players in this process are various immune cells, which work together during inflammation. The type of immune cells involved often varies depending on the harmful stimulus, influencing the outcome of the inflammatory response.

Immune cell trapping during allergic responses

Mast cells, residing in tissues and critical for initiating inflammation, are filled with granules containing pro-inflammatory substances. These granules are released upon encountering potential dangers, including allergens, causing allergic reactions. In many people, mast cells also react to seemingly harmless environmental factors, which then act as allergens and cause allergies. The interaction between mast cells and other immune cells at sites of allergic responses has been largely unexplored.

A research group at the MPI of Immunobiology and Epigenetics used specialized microscopy to visualize the real-time dynamics of activated mast cells and other cell types during allergic reactions in living mouse tissues. Led by Tim Lämmermann, since October 2023 Director at the Institute of Medical Biochemistry at the University of Münster, the team discovered a surprising interaction: neutrophils were found inside mast cells.

We could hardly believe our eyes: living neutrophils were sitting inside living mast cells. This phenomenon was completely unexpected and probably would not have been discovered in experiments outside a living organism and highlights the power of intravital microscopy."

Tim Lämmermann, Director, Institute of Medical Biochemistry, University of Münster

Pulling a neutrophil trick to trap neutrophils

Neutrophils are frontline defenders of our immune system, responding quickly and broadly to potential threats. They circulate in the blood and quickly exit blood vessels at sites of inflammation. They are well-equipped to combat invaders such as bacteria or fungi by engulfing the invaders, releasing antimicrobial substances, or forming web-like traps known as »neutrophil extracellular traps«. Additionally, neutrophils can communicate with each other and form cell swarms to combine their individual functions for the protection of healthy tissue. While much is known about neutrophils' role in infections and sterile injuries, their role in inflammation caused by allergic reactions is less understood.

"It quickly became clear that the double-pack immune cells were no mere coincidence. We wanted to understand how mast cells trap their colleagues and why they do it," explains Michael Mihlan, first and co-corresponding author of the study published in the journal Cell. Once the team was able to mimic the neutrophil trapping observed in living tissue in cell culture, they we were able to identify the molecular pathways involved in this process. The researchers found that mast cells release leukotriene B4, a substance commonly used by neutrophils to initiate their own swarming behavior.

By secreting this substance, mast cells attract neutrophils. Once the neutrophils are close enough, mast cells engulf them into a vacuole, forming a cell-in-cell structure that the researchers refer to as »mast cell intracellular trap« (MIT). "It is ironic that neutrophils, which create web-like traps made of DNA and histones to capture microbes during infections, are now trapped themselves by mast cells under allergic conditions," says Tim Lämmermann.

Recycled neutrophils to boost mast cell function

With the help of an international team, the researchers confirmed the formation of MITs in human samples and investigated the fate of the two cell types involved after trapping. They found that trapped neutrophils eventually die, and their remains get stored inside mast cells. "This is where the story takes an unexpected turn. Mast cells can recycle the material from the neutrophils to boost their own function and metabolism. In addition, mast cells can release the newly acquired neutrophil components in a delayed manner, triggering additional immune responses and helping to sustain inflammation and immune defense", says Michael Mihlan.

"This new understanding of how mast cells and neutrophils work together adds a whole new layer to our knowledge of allergic reactions and inflammation. It shows that mast cells can use neutrophils to boost their own capabilities – an aspect that could have implications for chronic allergic conditions where inflammation occurs repeatedly," says Tim Lämmermann. The researchers have already begun investigating this interaction in mast cell-mediated inflammatory diseases in humans, exploring whether this discovery could lead to new approaches to treating allergies and inflammatory diseases.

Source:

Max Planck Institute of Immunobiology and Epigenetics: Reference: News Medical: 

A snack in your garden? Fried elderflower recipe

This delicacy recipe has been cherished for many years. It was also noted in my grandmother's notebook with meticulous, small handwriting. Unassuming elderflowers can quickly transform into a snack that tastes and looks impressive.

Elderflowers are primarily associated with healthful syrups, liqueurs, or jams. However, before the dark berries appear on the bushes, they are brightened with small white flowers on expansive umbels.

Don’t walk by them indifferently; take them home. Not to make a bouquet but to the kitchen, where you can transform them into a delicious snack.

Elderflowers in pancake batter

Elderflowers aren't just a beautiful garden decoration but also a tasty ingredient for a simple snack. Elderflowers bloom briefly in June, so it's worth using them in the kitchen while they are available.

Preparing this dessert is incredibly easy, and the result will impress everyone. You only need a few ingredients and a bit of patience, and soon, you can enjoy this sweet delight. Umbels of elderflowers don't need to be washed, just cleaned of insects. If you place them on a clean cloth or paper towel, flower side down, the unwanted inhabitants will leave alone.

Ingredients:

Pancake Batter:

Instructions:

1. Pour the milk and water into a bowl. Add eggs, salt, and sugar, and mix well.
2. Add flour and mix until there are no lumps, forming a smooth batter.
3. Let the pancake batter sit for 30 minutes.
4. Heat the oil in a pan.
5. Dip the elderflower umbels. Hold them by the stem over the bowl to remove excess pancake batter.
6. Fry until golden. 
7. After frying, place on a paper towel to remove excess oil.

After transferring the elderflowers to a plate, cut off the stem—it's bitter. Sprinkle the fried elderflowers with powdered sugar. Enjoy! 

Story by Ewa Malinowska: Daily Wrap