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Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization
Shusei Hamamichi1, Takeshi Fukuhara2,3,4, Nobutaka Hattori2,3,4
1Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Abstract:
Toxins, while harmful and potentially lethal, have been engineered to develop potent therapeutics including cytotoxins and immunotoxins (ITs), which are modalities with highly selective targeting capabilities. Currently, three cytotoxins and IT are FDA-approved for treatment of multiple forms of hematological cancer, and additional ITs are tested in the clinical trials or at the preclinical level. For next generation of ITs, as well as antibody-mediated drug delivery systems, specific targeting by monoclonal antibodies is critical to enhance efficacies and reduce side effects, and this methodological field remains open to discover potent therapeutic monoclonal antibodies. Here, we describe our application of engineered toxin termed a cell-based IT screening system. This unique screening strategy offers the following advantages: (1) identification of monoclonal antibodies that recognize cell-surface molecules, (2) selection of the antibodies that are internalized into the cells, (3) selection of the antibodies that induce cytotoxicity since they are linked with toxins, and (4) determination of state-specific activities of the antibodies by differential screening under multiple experimental conditions. Since the functional monoclonal antibodies with internalization capacities have been identified successfully, we have pursued their subsequent modifications beyond antibody drug conjugates, resulting in development of immunoliposomes. Collectively, this screening system by using engineered toxin is a versatile platform, which enables straight-forward and rapid selection for discovery of novel functional antibodies.
Insights
Researchers developed a novel cell-based immunotoxin (IT) screening system to discover potent therapeutic monoclonal antibodies. This engineered toxin platform enables rapid identification of antibodies for targeted cancer therapies and drug delivery systems.
Area of Science:
- Biotechnology and Pharmaceutical Sciences
- Oncology and Cancer Therapeutics
- Immunology and Antibody Engineering
Background:
- Toxins are engineered into potent therapeutics like cytotoxins and immunotoxins (ITs) for targeted cancer treatment.
- Current FDA-approved ITs and ongoing clinical trials highlight their significance in hematological cancer therapy.
- Developing next-generation ITs and antibody-mediated drug delivery systems necessitates highly specific monoclonal antibodies for enhanced efficacy and reduced side effects.
Purpose of the Study:
- To introduce a novel cell-based immunotoxin (IT) screening system for the discovery of functional monoclonal antibodies.
- To demonstrate the system's capability in identifying antibodies with specific cell-surface recognition, internalization, and toxin-induced cytotoxicity.
- To showcase the system's versatility in selecting antibodies for advanced therapeutic applications, including antibody drug conjugates and immunoliposomes.
Main Methods:
- Application of an engineered toxin within a cell-based screening system.
- Differential screening under multiple experimental conditions to determine state-specific antibody activities.
- Selection of monoclonal antibodies based on cell-surface molecule recognition, cellular internalization, and toxin-mediated cytotoxicity.
Main Results:
- Successful identification of functional monoclonal antibodies possessing internalization capacities.
- Demonstration of the screening system's ability to select antibodies that induce cytotoxicity upon linkage with toxins.
- Validation of the system for discovering antibodies with state-specific activities through differential screening.
Conclusions:
- The engineered toxin-based cell-based IT screening system is a versatile platform for discovering novel functional antibodies.
- This system facilitates straightforward and rapid selection of antibodies crucial for next-generation immunotoxins and drug delivery systems.
- The identified antibodies with internalization capacities have been successfully modified for advanced applications like immunoliposomes.
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