BMP2-MIS Chimera Protein for Ovarian Cancer Apoptosis
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Solution Overview
Problem
Current ovarian cancer treatments have seen little evolution over three decades, with platinum-based chemotherapy eventually leading to chemoresistance, necessitating new therapeutic approaches, and attempts to produce native Müllerian-inhibiting substance (MIS) for treatment have been hindered by its complex nature and difficulty in expression.
Innovation Solution
Development of recombinant chimera proteins comprising MISIIR-binding segments grafted onto a bone morphogenic protein 2 (BMP2) framework, which can be expressed at high levels and induce apoptosis in cancer cells by binding to MISIIR and Type I receptors like ALK2, ALK3, and ALK6.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native MIS is produced for treatment, then therapeutic efficacy is achieved, but expression difficulty and complexity increase
Solution Approach 1:
The patent creates a chimera protein that copies the therapeutic function of native MIS by grafting the MIS binding region onto a BMP2 framework. This allows the protein to bind to MISIIR and activate the signaling pathway without requiring production of the complex native MIS molecule, thus maintaining therapeutic efficacy while simplifying manufacturing.
Solution Approach 2:
The patent uses a composite protein structure combining BMP2 framework with MIS binding region. This composite approach leverages the ease of BMP2 expression while incorporating the specific binding capability of MIS, achieving both manufacturability and therapeutic effectiveness.
2Reliability
If platinum-based chemotherapy is used, then initial treatment response is achieved, but chemoresistance develops
Solution Approach 1:
The chimera protein acts as an intermediary that activates the MISIIR/ALK signaling pathway, which is distinct from the platinum chemotherapy mechanism. This provides a novel therapeutic angle that can overcome chemoresistance by targeting a different signaling pathway that remains functional in resistant tumors.
3Productivity
If recombinant chimera proteins are expressed, then high expression levels are achieved, but protein complexity increases
Solution Approach 1:
The patent extracts only the essential binding region of MIS (residues 36-83) and grafts it onto BMP2, rather than producing the entire complex native MIS molecule. This extraction approach maintains the critical binding functionality while significantly reducing the overall protein complexity and improving expressibility.
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 chimera proteins effectively stimulate apoptosis in MISIIR-expressing cancer cells, offering a promising new treatment option for ovarian and other gynecological cancers by mimicking the MIS signaling pathway, potentially overcoming chemoresistance.
Implementation Method 1
MIS forms a ternary complex with MISIIR and ALK, activating the SMAD signaling pathway and triggering apoptosis
Implementation Method 2
activating the SMAD signaling pathway and triggering apoptosis, leading to regression of the female reproductive tract
Data Source
AI summary
Recombinant proteins that comprise a bone morphogenic protein 2 backbone onto which was grafted a Müllerian-inhibiting substance type II receptor binding region of the Müllerian-inhibiting substance protein are provided. These proteins bind to this receptor on the surface of epithelial cancer cells, and induce apoptosis of such cells. These proteins are useful, for example, in the treatment of cancers such as ovarian, uterine, endometrial, fallopian tube, breast, prostate, and lung cancers.