Anjum_Mod8_ Assignment

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Huda Anjum Module-8 Spring 2023 Module 8 Assignment 585.751.81 Immunoengineering 1. Your boss wants to develop a new food allergy diagnostic and thinks that a new biomarker will work better than looking at IgE levels and skin prick test. What can you tell your boss about what the diagnostic development process will look like? (This can look like an informal email – and can use bullet points) Include in your answer: (30 points)  Who needs to be involved in ideation  How it needs to be tested and validated  Target sensitivity and specificity  Available technologies, market, and cost  Source of sample and basic biology of a few potential targets  Total time required. Dear Boss, Thank you for considering a new food allergy diagnostic that focuses on biomarkers. Developing a new food allergy diagnostic using a new biomarker that is better than IgE levels and skin prick tests requires a thorough understanding of the underlying biological mechanisms involved in food allergies and the identification of specific markers that can accurately diagnose the condition. Here are some key points to keep in mind as we move forward: • Ideation: Developing a new diagnostic requires input from various stakeholders, including researchers, clinicians, and regulatory agencies. We need to identify potential biomarkers and evaluate their specificity and sensitivity in identifying food allergies. It would be helpful to involve a team of experts with diverse perspectives and expertise.  Experimental design: Once potential targets have been identified, the development team needs to design experiments to validate their efficacy as a biomarker for food allergy. This includes identifying the source of the sample, designing assays to measure the biomarker, and developing algorithms to analyze the data. • Testing and validation: Once we have identified potential biomarkers, we need to test and validate them in clinical settings. This involves testing the biomarker on a large sample size of patients with known food allergies and comparing the results to existing diagnostic tools to determine sensitivity and specificity. We will need to evaluate their performance in different patient populations, including those with known food allergies and those without. It will be important to ensure that the diagnostic is reliable, accurate, and reproducible. • Target Sensitivity and Specificity: The new biomarker needs to be highly sensitive and specific to food allergens to ensure that it can accurately diagnose food allergies. The sensitivity and specificity of the new biomarker need to be benchmarked against existing diagnostic tools to ensure its efficacy. We should aim for a sensitivity of at least 95% and a specificity of at least 90%. • Available technologies, market, and cost: There are different technologies available for biomarker detection, including ELISA, PCR, and mass spectrometry. We need to consider the costs, availability, and practicality of these technologies in the clinical setting. We also need to identify the market for our diagnostic and determine its potential impact on patient care. • Source of sample and basic biology of potential targets: To develop a reliable diagnostic, we need to identify the best source of the sample for testing. Blood or urine samples are common sources for biomarker detection. We also need to understand the basic biology of potential targets, such as cytokines or antibodies, to ensure that they are specific to food allergies. • Total time required: The timeline for developing a new diagnostic can vary depending on the complexity of the biomarker and the regulatory approval process. It could take several years to bring a new diagnostic to market. Thank you for considering this exciting new opportunity. I look forward to working with you on this project. Best regards, Huda Anjum 1

Huda Anjum Module-8 Spring 2023 2. How might the microbiota be used both as a diagnostic and therapeutic agent in autoimmunity? Why is this an attractive approach? What are limitations with using the microbiota as a diagnostic or therapeutic agent? (15 points) The microbiota refers to the diverse community of microorganisms that inhabit the human body, particularly in the gut. In recent years, there has been growing interest in the role of the microbiota in autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The microbiota can be used both as a diagnostic and therapeutic agent in autoimmunity in the following ways: 1. As a diagnostic agent: The composition of the microbiota can be used to diagnose autoimmune diseases. Research has shown that the microbiota of individuals with autoimmune diseases is different from that of healthy individuals. For example, individuals with multiple sclerosis have been found to have lower levels of certain beneficial bacteria in their gut compared to healthy individuals. These differences in the microbiota composition can potentially be used as diagnostic biomarkers for autoimmune diseases .[1] 2. As a therapeutic agent: Altering the composition of the microbiota through probiotics, prebiotics, or fecal microbiota transplantation (FMT) has been shown to have therapeutic potential in autoimmune diseases. For example, a recent study found that FMT from healthy donors can reduce symptoms and improve gut microbiota composition in individuals with inflammatory bowel disease (IBD). Another study showed that oral administration of a specific strain of bacteria reduced disease severity in a mouse model of multiple sclerosis. This approach is attractive because it is relatively non-invasive, and the microbiota can be manipulated through diet or probiotics without the need for drugs with potential side effects. However, there are also limitations to using the microbiota as a diagnostic or therapeutic agent. Some of these limitations include: 1. Complexity of the microbiota: The microbiota is a complex community of microorganisms, and it is challenging to identify the specific bacterial species or strains that are responsible for the observed effects. 2. Inter-individual variation: The microbiota composition can vary significantly between individuals, and it is challenging to establish a "normal" microbiota composition. This variability can make it difficult to establish reliable diagnostic or therapeutic targets .[1] 3. Safety concerns: The safety of fecal microbiota transplantation (FMT) is still being studied, and there is a risk of adverse effects, including infection and inflammation .[1] In conclusion, while the microbiota shows promise as a diagnostic and therapeutic agent in autoimmunity, there are still limitations to overcome before it can be widely used in clinical practice. 3. Compare and contrast cell engineering bacteria versus mammalian cell lines for therapeutic approaches. Also, give specific examples where you would use one versus the other. Finally, describe challenges for entry to market for these technologies. (15 points) Cell engineering has emerged as a promising strategy for developing novel therapeutic approaches. Bacteria and mammalian cell lines are two commonly used cell types for therapeutic applications. Here's a comparison between the two: 1. Cell Engineering of Bacteria: Bacteria are simple organisms that are relatively easy to manipulate genetically. They can be engineered to produce a wide range of molecules, including enzymes, antibodies, and small molecules, for use as therapeutics. Bacteria have several advantages over mammalian cell lines for therapeutic applications, including:  Bacteria are easy to grow and have a high production capacity, making them cost-effective for large-scale production.  They have a fast replication rate, allowing for rapid production of therapeutic molecules.  Bacteria can be engineered to express and secrete proteins, making them an attractive platform for the production of therapeutic antibodies. [4] Examples of bacterial therapies include:  Bacterial vaccines: Examples include the BCG vaccine for tuberculosis and the oral typhoid vaccine .[4] 2

Huda Anjum Module-8 Spring 2023  Bacterial enzymes: Examples include L-asparaginase, which is used to treat acute lymphoblastic leukemia, and collagenase, which is used to treat Dupuytren's contracture .[4]  Bacterial proteins: Examples include streptokinase, which is used to treat blood clots, and interferons, which are used to treat viral infections and cancer .[4] 2. Cell Engineering of Mammalian Cell Lines : Mammalian cell lines are commonly used for therapeutic protein production. They have several advantages over bacterial cells, including:  Mammalian cells can produce complex proteins with post-translational modifications that are similar to those found in human cells .[2]  They can be engineered to produce large quantities of a specific protein .[3]  Mammalian cells can be cultured under specific conditions to produce high yields of pure protein .[2] Examples of mammalian cell therapies include:  Monoclonal antibodies: Examples include adalimumab, which is used to treat rheumatoid arthritis, and rituximab, which is used to treat cancer .[2]  Recombinant proteins: Examples include insulin, which is used to treat diabetes, and erythropoietin, which is used to treat anemia .[2] Challenges for Entry to Market for Cell Engineering Technologies:  Regulatory hurdles: Developing a new therapeutic product requires compliance with rigorous regulatory requirements.  Manufacturing and scale-up challenges: Producing large quantities of the therapeutic product in a consistent and cost-effective manner is essential for commercial success .[3]  Intellectual property challenges: Protecting the intellectual property related to the therapeutic product is crucial for commercial success.  Market competition: There may be competition from existing therapeutic products, which could limit the market potential for a new product. In conclusion, both bacterial and mammalian cell lines have unique advantages and disadvantages for therapeutic applications. The choice of cell type depends on the specific therapeutic need and production requirements. However, entry to market for cell engineering technologies can be challenging, and regulatory, manufacturing, and intellectual property challenges must be considered. 4. a) Design a combination therapy that uses both biomaterials and a biologic-based therapeutic to treat one of the following allergic or autoimmune diseases: (40 points)  Asthma  Seasonal allergies  Multiple sclerosis  Rheumatoid arthritis  Chron’s disease In consideration of your design, specify your design constraints used such as: 1. Cost 2. Manufacturing 3. FDA regulations 4. Biophysical properties – such as size, shape, stiffness, etc. 5. Definition of success, such as a comparison to gold standard or acceptable side effects 6. Whether it is inspired by nature or biological mechanisms 3

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Huda Anjum Module-8 Spring 2023 To design a combination therapy that uses both biomaterials and a biologic-based therapeutic to treat a disease, I am choosing multiple sclerosis as my disease of interest. Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system, leading to demyelination of neurons and subsequent neurological deficits. The current treatment options for MS include disease-modifying drugs and immunosuppressants, which can have significant side effects and are not always effective. Therefore, there is a need for new and innovative treatments for MS. Our combination therapy for MS will use a biomaterial-based delivery system to deliver a biologic-based therapeutic to the affected area. Specifically, we will use a hydrogel-based delivery system that can be injected intrathecally to deliver a biologic-based therapeutic, such as a monoclonal antibody or a cytokine, directly to the central nervous system. The hydrogel-based delivery system will be designed to be biocompatible, biodegradable, and have a sustained-release profile, ensuring long-term efficacy and minimal side effects. Design Constraints: 1. Cost: We will use cost-effective materials and manufacturing methods to ensure that the therapy is affordable and accessible to patients. 2. Manufacturing: The hydrogel-based delivery system will be manufactured using scalable and reproducible methods to ensure that it can be produced in large quantities. 3. FDA regulations: We will ensure that our therapy complies with all FDA regulations and guidelines for safety and efficacy. 4. Biophysical properties: The hydrogel-based delivery system will be designed to have optimal biophysical properties, such as size, shape, and stiffness, to ensure effective delivery to the central nervous system. 5. Definition of success: The therapy should be compared to the gold standard of MS treatment, which is currently disease-modifying therapies (DMTs) that can reduce the frequency and severity of relapses and slow disease progression. The therapy should also have acceptable side effects. 6. Inspiration: The therapy can be inspired by biological mechanisms such as the role of microglia in tissue repair and the use of biomaterials for neural tissue engineering. . Combination therapy design: 1. Biologic-based therapeutic: Monoclonal antibodies targeting CD20, a protein expressed on the surface of B cells, have been shown to be effective in treating MS by reducing inflammation and preventing nerve damage. Therefore, a monoclonal antibody targeting CD20 can be used as the biologic-based therapeutic component .[5] 2. Biomaterials: Hydrogels composed of natural polymers such as hyaluronic acid can be used as the biomaterial component. These hydrogels can be loaded with factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which can promote tissue repair and stimulate axon growth. [6] The combination therapy can be administered via intrathecal injection, where the hydrogel containing the factors is delivered directly to the site of injury, while the monoclonal antibody is administered systemically. The hydrogel can provide a sustained release of the factors, promoting tissue repair over a longer period. The monoclonal antibody can reduce inflammation and prevent nerve damage systemically. Overall, the combination therapy using biomaterials and a biologic-based therapeutic can provide a targeted and sustained approach to treating MS, while minimizing systemic side effects. However, the cost of the therapy and FDA regulations for its use would need to be considered during its development and entry to market. b) Finally, compare and contrast the biomaterial and biologic design processes with the experience of this and last week’s exercises. The combination therapy and biomaterial therapeutic process design approaches have distinct differences in their focus, goals, and methodologies. Combination Therapy: 4

Huda Anjum Module-8 Spring 2023  Combination therapy involves the use of multiple therapeutic agents, often of different classes, to achieve a synergistic effect and improve treatment outcomes.  The focus of combination therapy is on optimizing the efficacy of treatment, reducing side effects, and preventing the development of drug resistance.  Combination therapy requires a deep understanding of the mechanisms of the disease, the pharmacokinetics and pharmacodynamics of the therapeutic agents, and the potential interactions between them.  The design process for combination therapy involves selecting the appropriate combination of agents, optimizing dosing regimens and administration routes, and evaluating the safety and efficacy of the treatment through preclinical and clinical studies. Biomaterial Therapeutic Process Design:  Biomaterial therapeutic process design involves the development of a material-based therapy that can directly interact with the patient's tissues or organs.  The focus of biomaterial therapeutic process design is on developing a material that can deliver a therapeutic agent to the site of action, improve drug efficacy, reduce toxicity, and promote tissue regeneration.  Biomaterial therapeutic process design requires a deep understanding of the properties and interactions of the materials being used, as well as their potential side effects and interactions with the human body.  The design process for biomaterial therapeutic process design involves selecting the appropriate material, optimizing its physical and chemical properties, designing the drug delivery mechanism, and evaluating the efficacy and safety of the treatment through preclinical and clinical studies. Overall, the combination of biomaterial and biologic design processes for developing a biomaterial-based delivery system for a biologic-based therapeutic for MS requires a different set of considerations and focuses than the exercise of designing a biomaterial therapeutic for TB. However, both approaches require a deep understanding of the disease mechanisms, material and biologic properties, and clinical translation considerations. Combination therapy focuses on optimizing the use of multiple therapeutic agents, while biomaterial therapeutic process design focuses on developing a material-based therapy to directly interact with the patient's tissues or organs. 5

Huda Anjum Module-8 Spring 2023 References: [1] Acharjee, Animesh, Singh, Utpreksha, Choudhury, Saptamita Paul and Gkoutos, Georgios V.. "The diagnostic potential and barriers of microbiome-based therapeutics" Diagnosis, vol. 9, no. 4, 2022, pp. 411- 420. https://doi.org/10.1515/dx-2022-0052 [2] Lai, Tingfeng et al. “Advances in Mammalian cell line development technologies for recombinant protein production.” Pharmaceuticals (Basel, Switzerland) vol. 6,5 579-603. 26 Apr. 2013, doi:10.3390/ph6050579 [3] Zhu, Marie M. et al. “Industrial Production of Therapeutic Proteins: Cell Lines, Cell Culture, and Purification.” Handbook of Industrial Chemistry and Biotechnology 1639–1669. 3 May. 2017, doi:10.1007/978-3-319- 52287-6_29 [4] Omer, Rabia et al. “Engineered Bacteria-Based Living Materials for Biotherapeutic Applications.” Frontiers in bioengineering and biotechnology vol. 10 870675. 28 Apr. 2022, doi:10.3389/fbioe.2022.870675 [5] Milo, Ron. “Therapies for multiple sclerosis targeting B cells.” Croatian medical journal vol. 60,2 (2019): 87-98. doi:10.3325/cmj.2019.60.87 [6] Gold, Stefan M et al. “Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls.” Journal of neuroimmunology vol. 138,1-2 (2003): 99- 105. doi:10.1016/s0165-5728(03)00121- 8 6

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