Biologics are drugs derived from complex molecules like antibodies. Over the last two decades they have re-emerged as game-changers in the treatment of diseases like rheumatoid arthritis, cancer, infectious diseases, and diabetes. As we enter a new era of biologics, it is important to understand the development to date, the bioanalytical challenges, and solutions.

The Rise of Biologics as Therapeutic

The advent of biologics began in the 1970s, marking a pivotal shift in the therapeutic landscape. This transition was driven by the development of immunotherapy, such as recombinant interleukin-2 or injection of autologous LAK cells (Lymphokine-activated killer cells) or TILs (Tumor infiltrating lymphocytes) in melanoma patients, and the subsequent creation of therapeutic antibodies. These antibodies, engineered to bind to specific epitopes on target proteins, catalyzed a move towards more precision-targeted treatments, reducing unwanted off-target effects commonly seen with smaller molecules or classical chemotherapies. In essence, biologics offered a superior solution in treating conditions needing immune system modulation, a domain where small molecules typically lacked effectiveness.

While the initial promise of biologics was encouraging, with the FDA-approval, in 1986, of Muromonab, an immunosuppressant murine monoclonal anti-CD3 antibody given to reduce acute rejection in patients with organ transplants, some setbacks also occurred. Earlier versions, such as monoclonal antibodies, suffered from safety and immunogenicity concerns. However, the development of chimeric and humanized antibodies generated by recombinant DNA technologies, mitigated these issues, finally resulting in more than 150 regulatory-approved antibody therapies in 2022. Recently, antibodies have played a critical role as therapeutic and prophylactic agents against human viruses, with FDA approval of biologics for COVID-19, RSV, HIV, and Ebola infections. Currently, the field of biologics is exploding with strategies to boost antibody potency, specificity, stability, solubility, and broad activity against multiple targets, enhancing FC-mediated functions, and facilitating the delivery of therapeutic payloads (toxic substances, cytotoxic agents, radioactive molecules and cytokines).

Beyond their specificity and effectiveness, the complexity of producing copies also created a unique market niche, fostering ownership and intellectual property protection, and consequently a robust financial value. Today, even though traditional drugs comprise 70% of prescriptions, the financial muscle is powered by biologics, particularly monoclonal antibodies dominating the top 10 market compounds.

Deepened understanding of the immune system and its pathways, coupled with progress in analytical technologies for decoding biologics’ actions and monitoring biomarkers, has also been instrumental in unlocking the potential of biologics. A vivid illustration is the expansion of flow cytometry from three colors to over 40, enabling more precise characterization of cell populations.

Tackling Biologics Challenges

However, these scientific advances and the resulting medical breakthroughs come with challenges:

  • Costs: The high price of biologic therapies, like the $90,000 annual cost of Humira, the most prescribed biologic worldwide, poses concerns for health systems. While biosimilars promise to reduce costs significantly, new therapies, like cell therapies, could even run into millions annually, that potentially may be unsustainable in the long run.
  • Manufacturing Consistency: Unlike small molecules that can be synthesized on a large scale, genetically engineered biologics are produced in living cells. The manufacturing process for biologics is therefore more complex and raises concerns over batch consistency, contamination, and genetic drifts.
  • Measuring Biologics’ Effects: Biologics face rigorous testing to ascertain their safety and efficacy. However, their side effects, higher immunogenicity compared to small molecules, and difficulties in detection and quantification in bodily fluids – due to similarities with endogenous proteins – can pose unique challenges.

In the face of these challenges, particularly the third one, our company’s mission has always been clear: innovate, adapt and actively provide well thought-out bioanalytical solutions. Active Biomarkers was born from the merger of two biopharmaceutical firms driven by the need for enhanced expertise for bioanalytical characterization of their immunotherapeutic candidates. Initially guided by a world-class, senior advisory board we could immediately and efficiently address scientific inquiries and challenges. Over time our investment in staff, expertise, workflows, and technology has built a solid foundation to support clinical studies focused on these complex molecules.

KCAS and Active Biomarkers assembled an international team of bioanalytical experts and a comprehensive technological toolbox. Our focus: to stay at the forefront of novel scientific advancements, assess breakthroughs for bioanalytical use and to decipher the complex effects of biologics in clinical trials. This mission necessitates a rigorous evaluation of cutting-edge technologies as well as standardizing and validating a comprehensive set of methodologies – the backbone of our data’s accuracy and reliability. As part of this ongoing effort, we have successfully established a standardized ELISpot technology platform, applied strict methodologies to multiparametric flow cytometry, and pioneered sensitive immunoassays for monitoring immune cell analytes, proving highly successful in tracking events like cytokine storms. Building on our know-how in method development and our LBA technological platforms, we more recently jumped in the PK and ADA worlds.

By constantly raising awareness of the impact of sample logistics and pre-analytical handling on the quality and reliability of the data generated, we have built strong and trusting relationships with our customers. For one client that ended up with approximately 20% PBMC samples eligible for analysis in a Phase II clinical trial, a PBMC network was established to ensure more standardized and rapid PBMC processing. The outcome was transformative, with over 95% of samples subsequently qualifying for analysis.

At the other end of the workflow, recurring challenge lies in the lack of standardization in data analysis, that may lead to variability in test results. Here, we foresee a pivotal role for AI, particularly for tissue sample analysis via imaging techniques or to collate the results of multiple techniques around the same patient, but also in flow cytometry. Automated flow cytometry data analysis tools are being increasingly used to solve process bottlenecks, reproducibility issues, improve standardization of time-consuming manual analysis of multidimensional data sets.

Key Takeaways

Despite numerous challenges, biologics have a promising future, as evidenced by exciting new developments in inflammatory diseases, oncology, and neurodegenerative diseases. As a high-quality, science-first and customer-centric CRO, we’re committed to leading bioanalysis innovation, reminding that the true mark of progress is not just the avoidance of failure, but the determination to overcome it.

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