What is Multimodal in Drug Discovery?

Chemically modified biologics represent a sophisticated approach to drug design and development and the possibility of unlocking new therapeutic potentials, and are part of the broader area of multimodal drug discovery. These advancements give hope for the development of more effective and safer treatments for a wide range of diseases and enhance the lives of patients worldwide.

Within the domain of the biologics space, chemically modified biologics represent a subset of drugs that have been purposely altered through various chemical processes (like molecular glues, etc.) to enhance their therapeutic properties. By making targeted modifications to the structure of a biologic, chemists and biological researchers can create novel drugs that are a more effective and stable treatment for various diseases. Not only can modifications increase the therapeutic potential of a biological drug, but they can also help mitigate potential side effects and increase the overall tolerance of a drug when compared to no modifications.

The History of Multimodal Drugs

The journey of chemically modified biologics traces back to the early 1970s, when researchers first began exploring ways to enhance the efficacy and stability of protein-based therapeutics. A significant milestone occurred in 1977 when Davis and Abuchowski developed the process of PEGylation, attaching polyethylene glycol (PEG) to proteins, which marked the inception of modern chemically modified biologics. This innovation was crucial as it significantly increased the circulating half-life of proteins in the bloodstream, thus reducing immunogenicity and enhancing therapeutic efficacy. Over the decades, advancements continued with techniques such as glycosylation and conjugation further evolving in the 1990s, allowing for precise target identification and improved delivery mechanisms of biologic drugs. These modifications have paved the way for numerous breakthrough therapies in treating complex diseases, highlighting a pivotal evolution in pharmaceutical biotechnology.

The Growing Demand for Multimodal Drugs

The days of viewing drug discovery through the separate lenses of small molecules and large molecules are outdated. Today, the creation of new drugs in biopharma is increasingly multimodal, and leading-edge laboratories require a new approach that supports small-molecule, large-molecule, and new modality discovery workflows, including registration.

New modalities, such as recombinant proteins and peptides, engineered antibodies, and targeted cell and gene therapies, are critical drivers of biopharmaceutical industry growth. According to BCG, revenues from new-modality products increased by $60 billion over the past few years, while revenues from conventional products declined by $10 billion. Furthermore, BCG predicts that the percentage value of new modalities in the five-year forward pipeline between 2019 and 2023 will increase from 41% to 56%, far outpacing conventional ones. 

The Purpose of Multimodal Drugs

The purpose of chemically modifying biologics is fundamentally aimed at enhancing their clinical efficacy and safety. These modifications are meticulously designed to augment intrinsic properties of the biologic, such as stability and drug target precision, or to tailor the biologic to be more patient-friendly by improving its tolerability and safety profile. An exhaustive investigation into the core attributes of the biologic molecule—its pharmacokinetics, stability, targeting capabilities, and safety—is conducted before formulating any modification strategy.

The most common types of modifications employed to achieve these enhancements include:

PEGylation (Polyethylene Glycolylation): This technique involves attaching PEG chains to biologic molecules. By increasing the hydrodynamic size of the biologic, PEGylation helps extend the drug’s circulating life and reduce immunogenicity.

Glycosylation: The addition of sugar or carbohydrate molecules to specific proteins can significantly alter their solubility, stability, and immunogenicity, enhancing the protein’s therapeutic properties and half-life.

Conjugation: This method links a biologic molecule with another chemical entity, such as a drug, polymer, or radioactive substance. Conjugation can introduce new functionalities or create hybrid entities that combine the therapeutic effects of both components.

Chemical Modifications like Deamidation and Oxidation: Both spontaneous and intentional during manufacture and storage, modifications like deamidation and oxidation can alter the molecular structure of biologics, affecting their potency, stability, and safety.

Through these targeted modifications, biologics’ development focuses on enhancing the desired therapeutic effects and minimizing potential adverse reactions, making treatments more effective and accessible for patients. Recent advances in modification techniques continue to push the boundaries of biologic drug development, opening new avenues for treating various diseases with precision and efficacy.

The Role of Different Job Disciplines in Multimodal Drugs

In the realm of chemically modified biologics, the significance of multimodal discovery is paramount, serving as a linchpin in optimizing the therapeutic attributes of these complex molecules. Multimodal discovery embodies an interdisciplinary approach that amalgamates a wide array of scientific disciplines—including pharmacology, biochemistry, chemistry, and biotechnology—each contributing uniquely to the holistic development process. This integrative strategy is crucial for tackling the intricate challenges of disease treatment and understanding drug interactions within biological systems.

The involvement of pharmacologists is critical, as they elucidate the mechanisms of action of biologics and pinpoint potential modification sites that could enhance therapeutic efficacy or reduce adverse effects. Their deep understanding of how biologics interact with biological receptors, enzymes, and signaling pathways is instrumental in the molecular characterization of diseases and the strategic design of targeted therapies. This knowledge is especially valuable for identifying the optimal sites for chemical modifications and forecasting the ramifications of these changes on the drug’s performance and safety profile.

Biochemists and biotechnologists bring essential skills in manipulating and analyzing biological molecules. They spearhead the development of recombinant DNA technologies, which are crucial for expressing, purifying, and producing biologic drugs. Their expertise also extends to optimizing cell lines and expression systems to boost the yield and quality of these therapeutic proteins. Through sophisticated biotechnological processes, they can engineer biologic molecules to exhibit desired properties, such as enhanced stability, solubility, and bioactivity, which are critical for clinical success.

Chemists contribute fundamentally to the design and synthesis of chemical modifications that improve biologics. Their proficiency in organic chemistry and bioconjugation techniques is vital for creating novel chemical entities that can be conjugated to biologic molecules. This includes developing linker chemistries that attach targeting ligands, polymers, or small molecules to biologics, enhancing drug delivery and therapeutic impact. Chemists are also essential for optimizing synthesis conditions, purifying compounds, and developing analytical assays that ensure the quality and efficacy of the final chemically modified biologic products.

Together, these disciplines converge in a multimodal discovery process that leverages their diverse expertise and methodologies. This collaboration not only accelerates the development of effective therapies but also ensures a comprehensive understanding of the interactions and impacts of chemically modified biologics within biological systems. The role of each discipline is integral to the successful creation and implementation of innovative treatments that can address the complexities of modern diseases.

Multimodal Drug Examples

Adalimumab (Humira)

Adalimumab (sold under Humira and manufactured by AbbVie) is a monoclonal antibody targeting tumor necrosis factor alpha (TNF-α). It is used to treat various autoimmune disorders such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Although Adalimumab is not pegylated, it undergoes a proprietary formulation process that includes buffering agents and excipients to enhance its stability and prolong its half-life in the body. This strategic formulation addresses challenges associated with the short half-life and immunogenicity of unmodified antibodies, enabling more targeted and effective treatment.

Adalimumab has had a transformative impact on the treatment of autoimmune diseases, offering patients significant symptom relief and improved long-term disease control. The extended dosing interval and subcutaneous administration of Adalimumab improve patient convenience, leading to better long-term outcomes and enhanced quality of life for individuals living with these conditions.

Pegfilgrastim (Neulasta)

Pegfilgrastim is a chemically modified form of the drug Filgrastim (a granulocyte colony-stimulating factor) achieved through PEGylation. This modification increases the drug’s half-life, allowing for less frequent dosing, typically used to reduce the chance of infection in patients undergoing chemotherapy by boosting white blood cell counts.

Certolizumab pegol (Cimzia)

This biologic is a PEGylated monoclonal antibody that binds to tumor necrosis factor-alpha (TNF-α), similar to Adalimumab. However, its PEGylation enhances its pharmacokinetics, allowing it to remain in the bloodstream longer and requiring less frequent administration. It is used primarily in the treatment of rheumatoid arthritis and Crohn’s disease.

The Future of Multimodal Drugs

The future of chemically modified biologics appears highly promising, with ongoing advancements aimed at enhancing drug efficacy, reducing side effects, and broadening the spectrum of treatable conditions. Research continues to focus on developing more sophisticated modification techniques such as advanced PEGylation, site-specific conjugation, and innovative encapsulation methods that improve targeting and reduce immunogenic responses. Furthermore, the rise of personalized precision medicine will likely drive the creation of biologics that are custom-tailored to individual genetic profiles, enhancing treatment outcomes.

The integration of artificial intelligence, machine learning, and deep learning in biologic design is also expected to accelerate the discovery and optimization of these therapies. These developments suggest a dynamic and transformative path ahead for chemically modified biologics in therapeutic applications.

The Need For A Unified Software Approach For Multimodal Discovery

In the complex drug discovery landscape, integrating various modalities—from small molecules to large biologics—necessitates a unified approach. Many companies operate with segregated registration systems, one for small molecules and another for large molecules, which complicates multimodal discovery efforts. This separation can hinder the seamless integration of data, collaboration across disciplines, and adherence to regulatory standards. A unified registration system addresses these challenges by providing a single platform where researchers can manage all data, ensuring regulatory compliance, and fostering collaboration with a consistent source of truth.

The Sapio Platform exemplifies this integrated approach with its single materials management system that treats small-molecule, large-molecule, and multimodal entities uniformly as molecular materials. This system stores information and enhances it through seamless data visualization and traceability by linking sample management with registered entities. This integration allows chemists and biologists to collaborate effectively on the same platform, utilizing tools such as Sapio LIMS, Sapio ELN, and Sapio Jarvis to synchronize and analyze scientific data comprehensively across the laboratory informatics spectrum.

For new biotech ventures, adopting the Sapio Platform from the outset can catapult their entry into cutting-edge modalities of drug discovery, enabling them to leverage integrated insights and accelerate their research initiatives from day one. Meanwhile, established biopharma enterprises need to recognize the limitations and risks associated with disjointed, discipline-specific informatics systems. By transitioning to a unified lab informatics platform like Sapio, they can enhance their capabilities in pioneering multimodal drug discovery, optimizing their research outcomes, and staying at the forefront of innovation. This unified approach is not just about technological integration but also about creating an ecosystem where multidisciplinary teams can thrive and drive forward the development of novel therapeutics.

Frequently Asked Questions

What are the specific regulatory challenges associated with the approval of chemically modified biologics?

Chemically modified biologics, like other innovative therapeutic products, face several regulatory challenges that are often more complex than those for traditional drugs. The primary challenge is demonstrating the safety and efficacy of these modified molecules. Due to their enhanced complexity and the novelty of the chemical modifications involved (such as PEGylation or conjugation), regulators require extensive data to understand their behavior in the body, potential immunogenicity, and long-term effects. This requires comprehensive clinical trials and detailed characterization studies. Additionally, the manufacturing processes for these drugs are complex and must be meticulously controlled and validated to ensure consistency, stability, and purity of the final product. Regulatory agencies like the FDA or EMA may require additional data or impose stricter guidelines to manage these complexities, which can extend the approval timeline and increase development costs.

How do the costs of developing chemically modified biologics compare to other drug types?

The development costs for chemically modified biologics are typically higher than for traditional small molecule drugs. This is due to several factors including the complexity of the drug design, the advanced technologies required for their development, and the scale-up of manufacturing processes which often involve sophisticated biological systems and stringent conditions. Additionally, the clinical testing phase can be more expensive, as it may involve specialized assays to monitor the biologic’s behavior and modifications in the body. However, these costs are often justified by the potential for these drugs to address unmet medical needs with higher efficacy and possibly better patent protection, which can lead to significant market exclusivity and financial returns once the drug is approved.

Can you provide examples of how personalized medicine is currently utilizing chemically modified biologics?

Personalized medicine aims to tailor medical treatment to the individual characteristics of each patient, often based on genetic profiles. Chemically modified biologics are increasingly being integrated into personalized medicine strategies, especially in areas like oncology and autoimmune diseases. For example, certain engineered antibodies can be modified to target specific antigens present only in particular patient populations. An instance is the use of antibody-drug conjugates (ADCs) in cancer therapy, where antibodies specific to cancer cell antigens are linked to potent anti-cancer drugs. These ADCs deliver the drug directly to the tumor cells, minimizing side effects and improving efficacy for patients with specific tumor types. Another example is in the treatment of genetic disorders where specific modifications in biologics can enhance their uptake by target cells or tissues that are genetically predisposed to a disease, enhancing the therapeutic outcomes and reducing systemic exposure.