EMR2-TRBV19 Bispecific Antibodies for Lower-Cytokine AML Targeting
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Solution Overview
Problem
Current immunotherapies for acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) face challenges due to limited clinical activity, severe cytokine release syndrome, and significant toxicities owing to the broader expression of AML targets on healthy myeloid cells and nonhematopoietic tissues.
Innovation Solution
Development of bispecific antibodies that specifically bind to the G-protein-coupled receptor auto-proteolysis inducing (GAIN) domain and/or the GPCR proteolytic site (GPS) motif of epidermal-growth-factor-like module-containing mucin-like hormone receptor 2 (EMR2), with high affinity and specificity, and optionally targeting the T cell receptor TRBV19.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current immunotherapies target AML markers broadly, then they can engage T cells to kill cancer cells, but they cause severe cytokine release syndrome and significant toxicities to healthy cells
Solution Approach 1:
The patent applies local quality by creating a bispecific antibody with distinct binding specificities: one arm binds EMR2 on AML cells with high affinity, while the other arm binds TRBV19 on a specific subset of T cells. This localized targeting to a specific T cell subset (TRBV19+) reduces broad T cell activation and consequently decreases cytokine release syndrome and toxicities while maintaining anti-tumor efficacy.
Solution Approach 2:
The invention segments the T cell population by selectively engaging only the TRBV19+ subset through the bispecific antibody design. This segmentation allows for more controlled and specific immune activation compared to pan-T cell engagement, thereby reducing off-target effects and cytokine release syndrome while maintaining therapeutic efficacy against AML.
2Adaptability or versatility
If immunotherapies use broader AML targets, then they achieve wider cancer cell coverage, but they increase toxicity to healthy myeloid cells and nonhematopoietic tissues
Solution Approach 1:
The bispecific antibody employs local quality by achieving specific targeting through dual binding: EMR2 binding provides cancer cell specificity while TRBV19 binding restricts T cell engagement to a particular subset. This dual-specificity approach maintains adaptability to target AML cells while localizing the immune response to reduce toxicity to healthy myeloid cells and nonhematopoietic tissues.
3Object-affected harmful factors
If bispecific antibodies engage TRBV19+ T cells specifically, then they reduce cytokine release syndrome, but they require precise binding affinity to both EMR2 and TRBV19
Solution Approach 1:
The patent applies parameter changes by optimizing the binding affinity parameters of the bispecific antibody: the EMR2-binding arm is engineered with high affinity (KD of 0.01 nM to 5 nM) to ensure strong target engagement, while the TRBV19-binding arm is designed with moderate affinity (KD of 15 nM to 200 nM) to enable selective but controllable T cell engagement. This parameter optimization reduces cytokine release syndrome while maintaining therapeutic efficacy.
Data Source
AI summary
Provided herein are multispecific antibodies, including bispecific antibodies that specifically bind to EMR2 and TRBV19 (also known as Vβ17), and monospecific antibodies that specifically bind to EMR2, and multispecific antigen-binding fragments thereof. Also described are related polynucleotides capable of encoding the provided multispecific antibodies or multispecific antigen-binding fragments, cells expressing the provided multispecific antibodies or multispecific antigen-binding fragments, as well as associated vectors and detectably labeled multispecific antibodies or multispecific antigen-binding fragments. In addition, methods of producing and using the provided multispecific antibodies and multispecific antigen-binding fragments are described.