Why Are Monoclonal Antibodies the First Prime Targets for Animal-Free Testing at FDA?

On April 10, 2025, the FDA Roadmap to Reducing Animal Testing in Preclinical Safety Studies was released by the regulatory agency, amidst cheers from animal welfare groups and advocates of innovation in scientific research.

Previously, we provided an analysis of the FDA roadmap through the lens of PESTEL (political, economic, social, technological, ecological and legal) analysis. We also identified the health policy areas, including specific disease domains, that will benefit the most from this landmark new policy shift at the FDA.

Here, we list our top 10 reasons behind FDA’s choice to start with a common class of medications known as monoclonal antibodies (mAbs) as a first step in this important journey to improve human health and modernize the agency.

Notably, in an interview hosted by The Megyn Kelly Show on April 18, Marty Makary cited the example of monoclonal antibodies (mAbs), lamenting that one single mAb regulatory approval required the testing on 144 primates per the existing paradigm — which is unnecessary. This type of testing will be phased out in the new policy. The new commissioner also referred to a broader “problem” speaking about the use of animals in drug development. He outlined the existence of several technologies like AI, organoids and organ-chips that “should be replacing animal testing,” asserting that “he wants to see as much reduction in animal testing as humanly possible.”

These are the 10 key properties of mAbs that made them attractive for animal-free testing at the FDA:

1. Therapeutic relevance and immune system engagement. mAb-based therapies belong to the category of immunotherapy, which is very powerful in leveraging our own immune system to combat diseases. Immune responses are triggered in almost every serious illness (e.g., cancer, infectious diseases). Proper functioning of the immune system is also part of our everyday response to stressors and a determinant of healthy living.
   
   
2. Support for vaccine enhancement and optimization. Antibodies, while not vaccines themselves, can intensify and diversify the response to vaccines, prolonging their conferred protection and durability. As mAb-based therapies are bolstered in time and quality by the new FDA policy, the outcomes can be especially helpful for individuals with weakened immune system needing more therapeutic options.
   
   
3. Demonstrated failure of animal models in development. Decades of experience of antibody development using large animals have been disappointing and generally misleading. Sponsors are also realizing that they are prematurely discarding scores of potentially lifesaving drugs just because they fail in animals.
   
   
4. Versatility as a standalone or combination therapy. Antibodies are underscored by their flexibility of use. They can be deployed alongside a wide array of invasive and non-invasive therapies. Their versatility makes them a priority area and a clever choice for this program. For instance, antibodies can be used before (neoadjuvant) or after (adjuvant) a primary cancer treatment to help prevent recurrence, reduce side effects or improve outcomes.
   
   
5. High potential for widespread public health impact. Dozens of companies worldwide are actively developing hundreds of mAb-based therapies for a wide range of diseases (e.g., Cancers, Cardiovascular, Neurodegenerative, infectious diseases). Rapid advances in this area will likely create significant breakthroughs, fast. It will also encourage collaborations and promote healthy competitions, especially from small biotech companies avoiding animal testing because of cost, high-failure rate or ethical considerations.
   
   
6. Established scientific knowledge and development history. Antibodies have been around for more than two decades. In other words, these treatment modalities are neither based on outdated technologies nor founded on very novice ones (e.g., Crisper-based therapy that are still in early development). As such, there is considerable institutional memory’ and know-how in developing antibodies. Many lessons learned over the years by sponsors and regulators make mAbs a good ‘beachhead’ for this FDA program.
   
   
7. Compatibility with artificial intelligence and modeling. Given the structural, 3D nature of antibody design, mAb-manufacturing benefits greatly from artificial intelligence applications in refining the topography and improving the dimensional precision antibodies for better interaction with a target’s complex and dynamic structure.
   
   
8. Specificity of targeting and treatment outcome improvement. Ab-therapies are targeted and tailored as they seek to modify one defined and specific target (e.g., a cell surface receptor, a circulating protein) causing a disease or an abnormality. Any advances there triggered by this new FDA rule will lead to therapies with less side effects and more precision.
   
   
9. Cost-efficiency compared to animal-based testing. Large complex mammals, aside from unreliability to model human diseases, are cost prohibitive. Antibody testing typically requires 150 primates (av. $50,000 each), so a cohort will cost $7.5 million. Studies showed that this can be achieved with a fraction of the cost using non-animal testing methods. For instance, a cost comparison analysis by the Moderna showed that an experiment using animal-free Organ-chips cost $325,000 compared to $5.25 million using Non-Human Primates (NHPs), with experimental time reduced several folds when using Organ-chips.
   
   
10. Avoidance of misleading inter-species variability. Today, on average 92% of experimental drugs fail clinical trials after animal data justified their advancement to the clinical stage. The amount of waste in this process is incalculable. In monoclonal antibody testing, reducing the reliance on animals (poor predictors of safety and efficacy responses in humans) and shifting to human-relevant models instead will improve experimental outcomes.

Ostensibly, between all classes of drugs, mAb-based therapies suffer the most form species difference between animals and humans for this type of therapy seeks specific targets (e.g., cell surface receptors that could be differentially expressed in other species or even not present altogether), producing significantly misleading results. Case in point, a cell surface receptor (ACE2) that serves as a doorway in humans for coronaviruses to infect cells is unresponsive in many species of animals, complicating comparisons and testing. Relying on animal models can be in many instances catastrophic from the standpoint of saving time or generating actionable information.

Undoubtedly, FDA has a shortlist of additional classes of drugs where animal testing would be gradually phased out. For instance, predicting toxicity in the liver (or DILI, Drug Induced Liver Toxicity) is one critical and problematic area where New Alternative Methods like Organ-chips have been shown in credible studies to outperform safety predictions using animals. Furthermore, skin irritation, Acute toxicity in rats, The Hershberger bioassay (in castrated rats for androgenic and anti-androgenic testing to assess the effects of animals on the endocrine system) and ocular sensitivity assays are all prime targets for replacements with animal-free methodologies.

Implementing a clear, accountable, and transparent system of checks and balances built around the intentional use of innovative technologies in drug discovery, away from the deadweights of animal testing, is clearly underway at the FDA. It is expected that such important and significant reform to regulatory policy at the agency will bring relief to millions of Americans, reduce futile animal testing in the regulatory process, and streamline a prescription drug marketplace, which in 2023 was valued at more than $1.23 trillion.

Zaher Nahle, PhD, MPA, is the senior scientific advisor for Animal Wellness Action and the Center for a Humane Economy. He received his MPA from Harvard University and his PhD in physiology and biophysics from Stony Brook University/Cold Spring Harbor Laboratory (joint prog.). He is an award-winning scientist, consultant, and non-profit executive.