Humanized Anti-PVR ADCs for Selective Tumor Payload Delivery
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Solution Overview
Problem
Existing antibody-drug conjugates (ADCs) face significant toxicity issues due to non-specific targeting and off-target release, limiting their effectiveness in treating cancers, particularly hard-to-treat tumors.
Innovation Solution
Development of ADCs comprising humanized anti-PVR antibodies, such as NTX1088, conjugated with specific payloads like MMAE, MMAF, DM1, DM4, or SN-38, using linkers that ensure targeted delivery and release of toxins in cancer cells, minimizing damage to normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional ADCs are used for cancer treatment, then they can deliver cytotoxic agents to target cells, but they cause significant toxicity due to non-specific targeting and off-target release
Solution Approach 1:
The patent applies local quality by engineering the ADC to have different functional properties at different locations: the antibody portion provides specific binding to PVR on tumor cells, the linker provides stable attachment during circulation, and the payload provides cytotoxic activity only upon intracellular release. This spatial differentiation of functional qualities enables selective targeting while protecting normal tissues from toxicity
Solution Approach 2:
The patent employs parameter changes by optimizing multiple critical parameters of the ADC system: selecting payloads with appropriate cytotoxic potency and release characteristics, designing linkers with specific cleavage rates and stability, and engineering antibodies with optimized binding affinity to PVR. These parameter optimizations collectively enhance targeting specificity while minimizing off-target toxicity
2Productivity
If ADCs with high potent payloads are used to increase efficacy against resistant cancers, then therapeutic effectiveness improves, but systemic toxicity increases
Solution Approach 1:
The patent applies segmentation by dividing the therapeutic system into three distinct functional modules: the targeting antibody that directs the complex to tumor cells, the linker that controls payload delivery timing and location, and the cytotoxic payload that eliminates cancer cells. This segmentation allows each component to be independently optimized for its specific function, enabling high therapeutic effectiveness while containing systemic toxicity through precise spatial and temporal control of payload release
3Reliability
If murine antibodies are used for ADC development, then they show high binding affinity to PVR, but they induce strong immune responses in human patients
Solution Approach 1:
The patent employs parameter changes by modifying the antibody's amino acid sequence parameters through humanization. The murine antibody framework is replaced with human framework regions while preserving the complementary determining regions (CDRs) that provide PVR binding specificity. This parameter modification reduces immunogenicity while maintaining high binding affinity to PVR, enabling effective ADC therapy in human patients
Data Source
AI summary
The present invention provides antibody drug conjugates (ADCs) of humanized anti-PVR (CD155) and use thereof in treating diseases, in particular cancer.