CD28 Antibody Engineering to Avoid Super-Agonist Toxicity
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Solution Overview
Problem
Current anti-CD28 antibodies, such as TGN1412, exhibit a high toxicity profile due to super-agonistic activity leading to cytokine release syndrome, limiting their use in cancer therapy, and there is a need for antibodies with a more favorable toxicity profile that can also act as checkpoint inhibitors.
Innovation Solution
Development of human antibody molecules that bind CD28 without super-agonistic activity, providing a strong co-stimulatory signal and cross-reactivity with CTLA-4, which are specifically designed to enhance immune response against cancer without TCR/CD3 engagement.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional agonistic anti-CD28 antibodies are used, then T cell co-stimulation is enhanced, but super-agonistic activity causes cytokine release syndrome and high toxicity
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's binding characteristics to CD28. The engineered antibodies have altered affinity and specificity parameters compared to conventional agonistic antibodies, enabling strong co-stimulation without super-agonistic cytokine release. This is achieved through specific mutations in the antibody variable regions that tune the interaction parameters with CD28.
Solution Approach 2:
The patent implements local quality by creating antibodies with differential binding properties to different CD28 epitopes or related molecules. The engineered antibodies exhibit selective binding characteristics that provide strong co-stimulatory signals while avoiding the pathological effects associated with uniform high-affinity binding to all CD28 sites.
2Productivity
If antibodies are designed to provide strong co-stimulatory signal without TCR/CD3 engagement, then immune response is enhanced, but selectivity and control become more difficult
Solution Approach 1:
The patent applies universality by designing antibodies that can provide co-stimulatory signals through multiple mechanisms. The engineered antibodies not only bind CD28 but also cross-react with CTLA-4, providing dual functionality. This multi-functionality allows the antibody to enhance immune responses through both direct CD28 co-stimulation and checkpoint inhibition, simplifying the overall therapeutic approach.
Solution Approach 2:
The patent uses intermediary principles by introducing engineered antibodies as mediators that bridge CD28 and CTLA-4 pathways. These antibodies act as intermediaries that can simultaneously engage both receptors, providing coordinated immune modulation without requiring direct TCR/CD3 engagement, thus maintaining selectivity while enhancing efficacy.
3Adaptability or versatility
If antibody cross-reactivity with CTLA-4 is added, then checkpoint inhibition capability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies merging by combining CD28 agonistic activity and CTLA-4 checkpoint inhibition into a single antibody molecule. The engineered antibodies simultaneously possess both functionalities, eliminating the need for separate therapies. This consolidation simplifies manufacturing compared to producing and coordinating multiple separate antibody products.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antibodies provide a safer and more potent immune stimulation, enhancing cancer treatment efficacy by boosting the immune system and acting as checkpoint inhibitors, with reduced toxicity and improved co-stimulatory effects compared to existing antibodies.
Implementation Method 1
human antibody molecules which bind human CD28 and murine CD28
Data Source
AI summary
The application relates to the diagnosis and treatment of diseases, including cancer, chronic infectious diseases, autoimmune diseases, inflammatory disorders, as well as the prevention of transplant rejection. The invention provides, and involves the use of, antibody molecules that bind CD28 in a non super-agonistic manner and which also bind to CTLA-4. The antibody molecules may form part of a bispecific molecule which binds e.g. a tumor associated antigen or a further T cell antigen, such as CD3.