Anti-PRLR Antibody-Drug Conjugates with PBD Warhead
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Solution Overview
Problem
Current cancer therapies face challenges such as lack of selectivity towards cancer cells and development of treatment resistance, with existing targeted therapeutics like antibodies having limitations in efficacy and side effects.
Innovation Solution
Development of anti-prolactin receptor (PRLR) antibody drug conjugates (ADCs) comprising a cytotoxic agent linked to an anti-PRLR antibody via a specific linker, utilizing a pyrrolobenzodiazepine (PBD) warhead and a low drug-to-antibody ratio (DAR) of about 2, which specifically targets PRLR-expressing cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy is used, then cancer cells can be treated, but selectivity towards cancer cells is poor and side effects occur
Solution Approach 1:
The therapy is segmented into two distinct components: a targeting antibody that specifically binds to PRLR on cancer cells, and a cytotoxic drug payload. This segmentation allows the drug to be delivered selectively only to cancer cells expressing PRLR, avoiding damage to healthy cells and reducing side effects while maintaining treatment efficacy.
Solution Approach 2:
The antibody acts as an intermediary between the cytotoxic drug and the cancer cell. It specifically recognizes and binds to the PRLR antigen on the cancer cell surface, mediating the selective delivery of the drug payload to the target cell while sparing healthy cells that do not express the target antigen.
2Object-affected harmful factors
If targeted therapeutics like antibodies are used, then selectivity is improved, but efficacy is limited
Solution Approach 1:
The invention merges the selective targeting capability of antibodies with the potent cytotoxic activity of chemotherapeutic agents into a single conjugate molecule. This combination allows the therapeutic to maintain high selectivity for cancer cells while delivering sufficient cytotoxic payload to achieve effective anti-tumor activity.
Solution Approach 2:
The ADC is a composite material combining three distinct functional components: the antibody portion for target recognition and binding, the linker for stable conjugation and controlled release, and the cytotoxic payload for killing cancer cells. This composite structure integrates the advantages of each component to overcome the limitations of using antibodies alone.
3Reliability
If high drug-to-antibody ratio is used, then cytotoxic potency is increased, but stability and selectivity are reduced
Solution Approach 1:
The invention optimizes the drug-to-antibody ratio parameter to a specific range (about 1.8 to 2.4, preferably about 2.0). This parameter optimization balances the competing requirements of sufficient cytotoxic potency and adequate stability, achieving effective anti-tumor activity while maintaining binding specificity and reducing off-target effects.
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 anti-PRLR ADCs demonstrate potent anti-tumor activity with improved efficacy compared to auristatin-based ADCs, maintaining binding specificity to PRLR and showing effectiveness in treating cancers with abnormal PRLR expression levels, even at lower PRLR-expressing tumors.
Implementation Method 1
ADCs bind to target cells via their antibody portions
Implementation Method 2
ADCs bind to target cells via their antibody portions and become internalized
Data Source
AI summary
Provided are antibody drug conjugates that bind PRLR, in particular human PRLR, their methods of making, and uses thereof.