This article is the first in a three-part series exploring the stages of the biologics drug development pipeline— from early-phase research and target identification to lead generation and optimization. Part 1 provides an overview of the pipeline stages, highlights early-phase mAb development and industry trends, and lays the groundwork for understanding how clinical-grade reference products can strengthen early-phase research and accelerate progress.
Biotherapeutic pipelines are rapidly growing across multiple therapeutic areas showing remarkable success rates — but what does this mean for the future of drug development?
In this evolving landscape, clinical-grade reference molecules offer more than just benchmarks—can they be the key to validating methods, standardizing performance, and fast-tracking next-generation monoclonal antibody (mAb) drug development?
Early development stages are crucial for defining the pipeline, Decisions made here often determine which candidates advance and how efficiently they reach clinical trials.
Let’s dive into the evolving therapeutic mAb landscape and explore how clinical-grade reference mAbs can empower CROs and CDMOs to accelerate early development and unlock new possibilities.
The stages of the biologics pipeline
The drug discovery process is typically initiated by an unmet medical need or by limitations in existing therapies, such as insufficient efficacy or safety concerns.
Drug repurposing is also gaining traction wherein pre-existing therapeutic molecules are investigated for novel therapeutic applications. To translate medical needs into viable therapies, researchers rely on a structured discovery process that moves systematically from target validation to candidate optimization.
This includes the discovery phase, preclinical evaluation, clinical trials and commercialization:
Discovery phase
This phase begins with target identification and target validation to ensure biological relevance and therapeutic potential. Candidate mAbs are screened for interaction with the target, producing initial hits. These hits are refined into leads with improved drug-like qualities through iterative testing, focusing on potency, selectivity, and basic pharmacological properties.
At this stage, early insights are gained into mechanism of action, target engagement, and structure–activity relationships, though comprehensive safety and efficacy profiles are not yet established.
Preclinical phase
Following the selection of promising leads, the preclinical phase focuses on systematically evaluating safety, toxicity, pharmacokinetics (PK), and pharmacodynamics (PD). This involves a combination of in vitro and in vivo studies to assess toxicity, absorption, distribution, metabolism, and excretion (ADME), along with formulation development and efficacy modelling in non-human systems.
The data generated in this stage provide the foundation for regulatory submissions, demonstrating safety and proof-of-concept efficacy to justify progression into human clinical trials.
IND submission
The Investigational New Drug (IND) submission marks the transition from preclinical research to human testing. This application includes preclinical safety and pharmacology data, details on drug chemistry and manufacturing, and clinical trial protocols.
Regulatory authorities, such as the FDA, review the IND to ensure studies are scientifically sound and that participants are not exposed to undue risk. INDs may be submitted for commercial development, non-commercial research, or under special provisions such as emergency or expanded access.
Clinical trials
Once the IND is approved, clinical trials begin in humans and progress through three phases.
- Phase I focuses on safety, tolerability, and basic pharmacology in a small group of healthy volunteers or patients.
- Phase II expands to 100–300 patients to evaluate efficacy, optimize dosing, and continue safety assessments.
- Phase III involves several hundred to several thousand patients, confirming efficacy, monitoring side effects, and comparing the investigational drug against existing standards of care.
Across all phases, trials must follow strict regulatory and ethical requirements, including IRB oversight and informed consent, to ensure participant safety and scientific rigor.
Commercialization
The final step before market entry is the submission of a Marketing Authorisation Application (MAA) to the EMA, a Biologics License Application (BLA) to the FDA, or an equivalent filing with other regulatory agencies worldwide.
This comprehensive dossier integrates all preclinical, clinical, manufacturing, and labelling data to demonstrate the biologic’s safety, efficacy, identity, purity, and potency. Regulatory review involves detailed data assessment, inspections of manufacturing sites, and, in some cases, advisory committee input. Approval enables the biologic to be commercially distributed and prescribed for clinical use.
Early-phase mab development: Key industry trends and the role of reference products
Advancing a monoclonal antibody (mAb) candidate from discovery through commercialization is a long and resource-intensive journey, often spanning 10–15 years.
Given the time and investment required—and the high risk of attrition along the way—it is vital for research teams and CRO partners to focus their efforts strategically in the early phases.
Today, several new trends are reshaping how early-phase mAb development is approached:
Advances in Antibody Engineering and Modalities
Innovations in Fc engineering, glycoengineering, and half-life extension are improving antibody specificity, safety, stability, and manufacturability. These advances have also enabled new formats, including high DAR antibody–drug conjugates (ADCs), bispecifics, nanobodies, Fc-fusions, and IgM-based therapeutics, driving a much broader and more versatile biologics landscape.
Improved expression and manufacturing platforms
Advances in cell-line engineering, high-throughput expression systems, and continuous manufacturing approaches are enabling faster production of early candidates at higher yields and with greater consistency, critical for early testing and scale-up.
Combination strategies
Mab derivatives are increasingly being designed or optimized for use alongside checkpoint inhibitors, cytokines, CAR-Ts, or small molecules, creating synergistic effects and improving therapeutic outcomes.
Integration of artificial intelligence (AI)
AI is accelerating discovery and optimization by modelling antibody structures, predicting antigen interactions, and generating novel candidates. These tools reduce timelines and costs while improving success rates in early development.
Focus on developability and manufacturability
Early assessment of properties such as solubility, aggregation risk, immunogenicity, and stability is now routine, reducing costly late-stage failures.
As antibody pipelines expand, ongoing innovation in design and technology will continue to shape the pace and direction of mAb-based drug development.
For researchers and CROs advancing these therapies, leveraging platform knowledge is essential to deepen understanding of structure-function relationships and to make informed go/no-go decisions.
This is where reference molecules come in.
The effective use of well-characterized reference molecules provides the foundation for this approach, reducing risk, enhancing comparability, and enabling smarter, faster development.
How clinical-grade reference products strengthen early-phase development
Approved therapeutic (or ‘clinical-grade) molecules have well-characterized structural and functional profile. Their known Fab-mediated antigen binding and Fc-driven immune effector functions offer valuable reference points when developing new molecules and exploring novel mechanisms of action.
By anchoring new research to validated benchmarks, clinical-grade reference products ensure that early-phase development is both scientifically rigorous and positioned to advance the most promising candidates into clinical trials.
Depending on the context, clinical-grade reference drugs can serve multiple roles, including:
- Positive controls for target binding assays
- Isotype controls
- Parent molecule controls for ADCs, bispecifics, CARs, antibody fragments, and other antibody formats
- Reference standards for epitope mapping
- Reference for Fc region function and glycosylation profiles
- Structural and functional standard for screening parameters
- Comparator for potency, specificity, and functional activity
- Basis for in vitro and in vivo analytical method development
- Well-characterized standards for training and validating AI models
Why does this matter for CROs and CDMOs?
For CROs and CDMOs working in early-phase development, clinically approved reference molecules are strategic tools. Leveraging these well-characterized molecules allows you to build on validated biological frameworks, minimizing scientific and technical uncertainties.This approach shortens iteration cycles by providing benchmark comparators that help quickly identify promising candidates and assess their biological relevance.
Reference molecules can guide your design and development decisions throughout various stages of the discovery phase, empowering you to advance candidates more efficiently:
- Screen Candidate mAbs
Using reference molecules in screening enables better comparison of novel monoclonal antibody candidates against clinically validated profiles, improving the reliability and efficiency of hit selection.
- Quality Target Product Profile (QTPP)
Reference molecules provide a clear standard of the desired quality attributes and guide the formulation of the QTPP, helping align product development with clinical efficacy and safety expectations early in the pipeline.
- Lead Optimization
The presence of a reference molecule informs lead optimization by setting known pharmacokinetic and pharmacodynamic targets, enabling rational design and modification to enhance efficacy, stability, and safety.
- Analytical Development
Reference molecules facilitate the development of robust analytical assays, serving as controls and standards to ensure precise characterization of candidate molecules and monitoring of critical quality attributes.
- Formulation Development
Reference molecules help in formulating novel candidates by offering proven formulations as templates, reducing development risk and accelerating time frames by applying existing knowledge on stability, solubility, and delivery.
Conclusion
In a landscape where speed and precision are equally critical, clinical-grade reference products provide the quality and consistency needed to de-risk early development.
By anchoring your innovation to trusted benchmarks, researchers, CROs, and CDMOs can accelerate discovery, optimize candidates, and bring next-generation therapies to patients with greater confidence.
Partners like Evidentic make this possible by providing FDA-andEMA-approved biologics as research consumables — ensuring your progress in antibody engineering and novel modalities rests on the strongest, most trusted foundations.
References:
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- Cheng J, Liang T, Xie XQ, Feng Z, Meng L. A new era of antibody discovery: an in-depth review of AI-driven approaches. Drug Discov Today. 2024;29(6):103984. doi:10.1016/j.drudis.2024.103984
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