Monoclonal Antibodies Targeting Processed Trop-2 to Reduce On-Target Toxicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current targeted anticancer therapies face challenges due to on-target toxicity caused by antigen expression in normal tissues, limiting the use of high-potency therapeutics, as seen in cases like bivatuzumab mertansine and BAY794620, where skin and gastrointestinal toxicity occurred, respectively, and anti-Trop-2 therapies like PF-06664178 showed excess toxicity.
Innovation Solution
A platform is developed to obtain monoclonal antibodies that specifically bind to tumor-specific, post-translationally processed forms of Trop-2, utilizing immunization and screening methods to maximize epitope heterogeneity and differentiate between tumor and normal tissue recognition, thereby reducing toxicity and improving therapeutic index.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If monoclonal antibodies are designed to target Trop-2 for anticancer therapy, then antitumor potency is improved, but on-target toxicity occurs due to Trop-2 expression in normal tissues
Solution Approach 1:
The patent applies local quality by creating antibodies with different binding specificities针对不同加工形式的Trop-2。通过筛选识别未加工形式和加工形式的抗体，使得抗体能够选择性结合肿瘤细胞中的加工形式，而对正常组织中的未加工形式不结合或低结合，从而在局部（肿瘤组织）实现高 potency，在正常组织实现低毒性
Solution Approach 2:
The patent changes the binding parameter of antibodies from recognizing unprocessed Trop-2 to recognizing processed Trop-2 forms. This parameter change in antibody specificity allows differentiation between tumor cells (expressing processed forms) and normal cells (expressing unprocessed forms), thereby improving the therapeutic index by maintaining antitumor potency while reducing on-target toxicity
2Reliability
If high-potency therapeutics are used to target Trop-2, then therapeutic effectiveness is improved, but toxicity in normal tissues increases
Solution Approach 1:
The patent segments the Trop-2 antigen population into two distinct groups: unprocessed forms in normal tissues and processed forms in tumor tissues. By developing antibodies that specifically target the processed forms, the therapy can be segmented to affect only tumor cells while sparing normal cells, thereby maintaining high therapeutic effectiveness while reducing toxicity
Solution Approach 2:
The patent uses processed Trop-2 forms as an intermediary marker that is uniquely present in tumor cells. Antibodies targeting this intermediary form act as a selective mediator that delivers therapeutic effect only to tumor cells expressing the processed form, while normal cells expressing the unprocessed form are spared, thus improving the reliability-toxicity ratio
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
This approach allows for the design of novel targeted drugs with high antitumor potency and low on-target toxicity by selectively targeting tumor cells while sparing normal cells, as demonstrated by the ability of generated monoclonal antibodies to bind preferentially to processed Trop-2 in tumors versus normal tissues.
Implementation Method 1
monoclonal antibodies that bind with high affinity processed, tumor-specific forms of proteins
Data Source
AI summary
The present invention consists of a platform to obtain monoclonal antibodies that bind with high affinity processed tumor-specific forms of proteins. The platform is characterized by immunization methods that use as immunogenic material the processed target protein and domains thereof, expressed endogenously or in heterologous systems making use of various host cells, and screening methods that identify the antibodies that recognise and bind specifically and differentially the processed tumor-specific protein versus the same protein as expressed by normal tissues. As an example, the use of the platform is described to obtain specific antibodies for the processed tumor-specific form of Trop-2. The platform can be used to obtain targeted anticancer pharmaceutical products with an improved therapeutic index thanks to the reduction of on-target toxicity against normal tissues. The platform can also be used to obtain reagents for use in the diagnosis, prognosis and monitoring of tumors and metastases.