DARPin CD33 Engagers Reduce AML Toxicity
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Solution Overview
Problem
Current therapies for acute myeloid leukemia (AML) face challenges such as high mortality rates, treatment resistance, severe side effects, and on-target/off-tumor toxicities due to high affinity of antibody-based treatments for CD33, leading to a need for new CD33-specific binding proteins with improved toxicity profiles and therapeutic windows.
Innovation Solution
Development of recombinant binding proteins with ankyrin repeat domains that specifically target human CD33, which can be combined with other functional moieties like binding moieties for immune cells, half-life extending agents, or cytotoxic agents to enhance therapeutic efficacy while minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody-based treatments with high affinity for CD33 are used, then therapeutic efficacy against AML cells is improved, but on-target/off-tumor toxicity and severe side effects occur
Solution Approach 1:
The patent changes the molecular structure parameter from conventional antibodies to ankyrin repeat domain proteins (DARPins), which provides high affinity and specificity for CD33 while reducing off-target effects and toxicity associated with traditional antibody-based therapies
Solution Approach 2:
The DARPin proteins are engineered with specific local binding regions that target CD33 with high precision on AML cells, while the overall protein structure maintains properties that reduce systemic toxicity and off-tumor effects compared to full-length antibodies
2Reliability
If gemtuzumab ozogamicin (anti-CD33 monoclonal antibody conjugated to calicheamicin) is used, then cytotoxic activity against AML cells is improved, but hematologic and hepatic toxicity increases
Solution Approach 1:
The patent extracts the essential binding function from conventional monoclonal antibodies and implements it using smaller ankyrin repeat domain proteins, which can be conjugated to cytotoxic agents with improved pharmacokinetic properties and reduced toxicity profiles
Solution Approach 2:
The DARPin proteins have smaller molecular weight and different metabolic pathways compared to full-length antibodies, leading to altered clearance rates and reduced accumulation in toxic organs, effectively creating a shorter-lived therapeutic agent with reduced long-term toxicity
3Reliability
If CAR-T cell therapy targeting CD33 is used, then T cell cytotoxicity against AML cells is improved, but cytokine release syndrome and broad side effects on non-AML cells occur
Solution Approach 1:
The patent uses DARPin proteins as intermediary binding agents that can engage CD33 on AML cells and recruit immune cells or deliver cytotoxic payloads more selectively, avoiding the systemic immune activation and cytokine release syndrome associated with CAR-T cell therapy
4Reliability
If T cell engager bispecific antibodies are used, then functional connection between T cells and tumor cells is improved, but production costs increase and severe side effects occur
Solution Approach 1:
The patent segments the complex bispecific antibody structure into smaller modular DARPin protein components, each with specific binding functions, which simplifies production while maintaining the ability to engage both T cells and CD33-expressing tumor cells
Data Source
AI summary
The present invention relates to recombinant binding proteins comprising an ankyrin repeat domain, wherein the ankyrin repeat domain has binding specificity for human CD33, in addition, the invention relates to nucleic acids encoding such recombinant binding proteins, pharmaceutical compositions comprising such proteins or nucleic acids, and the use of such binding proteins, nucleic acids or pharmaceutical compositions in methods for treating or diagnosing diseases, such as cancer, e.g., acute myeloid leukemia (AML), in mammal, including a human.