The discovery and subsequent generation of engineered antibodies present an interesting paradox: a revolutionary treatment conducted by academic and industry labs, alike, and unique challenges associated with their human-specific molecular function. The researchers at JAX have developed a comprehensive humanized mouse platform to test and predict clinical stability, efficacy, and immunotoxicity. Here’s how researchers can use this platform to obtain critical information that can be used in an IND filing and design a clinical trial.
The discovery and subsequent generation of engineered antibodies present an interesting paradox: a revolutionary treatment conducted by academic and industry labs, alike, and unique challenges associated with their human-specific molecular function. These engineered antibodies have proven useful as either technology platforms or commercialized to generate novel therapeutics (Labrijin et al., 2019). Antibodies developed as therapeutics have shown significant promise for several disease areas, including cancer, autoimmune disease, infectious diseases, and many more. However, testing these antibodies for stability, efficacy, and safety before clinical trials has been complicated. Obtaining accurate preclinical in vivo data is prudent to translate into successful clinical studies (Glassman et al., 2019).
As a potential solution, the JAX researchers have developed a comprehensive humanized mouse platform to test and predict clinical stability, efficacy, and immunotoxicity of engineered antibodies. Why a humanized mouse model? You ask. Humanized mouse models, which have been engrafted with either human peripheral blood mononuclear cells (PBMCs) or hematopoietic stem cells (HSCs), have been widely used in preclinical research (Read our latest blog about the basics of humanized mice). As part of the JAX commitment to bringing the most innovative models and services, we examined and observed how the use of the JAX humanized mouse portfolio can predict critical characteristics of the candidate therapeutic, providing crucial information for clinical design trials. At a recent and colleagues from JAX presented their most recent study on this platform.
Testing clinical stability
An antibody’s half-life is crucial data to obtain, as it has implications for dosing regiments and cost. A longer half-life for a therapy correlates to reduced patient dosing, increased efficacy of the molecule. It stands a greater likelihood of being approved by a regulatory agency, such as the Food and Drug Administration (FDA) in the US (for more information on antibody half-life measurements, click here).
The JAX platform consists of humanized mouse models that are deficient in murine and express human at different levels. Developed by JAX professor Derry Roopenian, Ph.D., these mice allow for the generation of faster, clinically-relevant data for antibody stability and the testing of various Fc-domain albumin-conjugate, or therapeutic carried by albumin used in multiple therapeutic areas.
To predict Rituximab’s clearance in humans, the authors utilized the Tg32 JAX model to determine the clinical clearance. They observed that in the model, they were able to see the similar clearance of Rituximab in mice as seen in humans (see figure 1).
The authors then tested the in vivo efficacy. As shown in figure 2, using HSC-engrafted NSG™-IL15 mice, Rituximab treatment inhibited tumor growth in two independent studies.
And lastly, the authors were able to predict the combinatorial effect of Rituximab and a bispecific antibody. They observed that combining the two therapies enhanced the release of proinflammatory cytokines but did not also increase the antitumor activity (refer to figure 3).
Humanized mice are crucial in the drug development pipeline, and especially in the development of engineered antibodies. With JAX transgenic mouse models and humanized mice, the authors observed critical characteristics, including clearance, efficacy, and immunotoxicity. Using Rituximab as an example, the authors have shown how JAX cutting-edge models and preclinical services can identify the most promising candidates and facilitate the study design.
Visit the JAX Humanized Mouse Page to learn more about the extensive portfolio of models and services that can predict stability, efficacy, and safety.
Blog: Why humanized mice?
Using Humanized In Vivo Models for Preclinical Antibody Development: A Case Study
Glassman PM, Balthasar JP. 2019. Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development. Drug . : 10.1016/j.dmpk.2018.11.002. [PMID: 30522890]
Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. 2019. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug . : 10.1038/s41573-019-0028-1. [PMID: 31175342]