Bispecific Binding Agent Nucleic Acid Spacer Design
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Solution Overview
Problem
The production of bispecific dual binders, such as bispecific antibodies, is complex and requires sophisticated techniques due to the need for precise chemical coupling and purification, and existing methods often result in lower affinity for non-target tissues while maintaining high avidity for target tissues.
Innovation Solution
A binding agent of the formula A - a':a - S - b:b' - B:X(n) is developed, where A and B are monovalent binders of different specificity linked by a spacer of at least 1 nm in length, allowing for simultaneous binding to two different epitopes without interference, and a functional moiety X is bound covalently or via a binding pair to one of the binders or the spacer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bispecific antibodies are produced using conventional chemical coupling methods, then high avidity for target tissues can be achieved, but the production process becomes complex and requires sophisticated purification steps
Solution Approach 1:
The patent introduces a nucleic acid-based intermediary system where single-stranded DNA or RNA sequences serve as mediators to connect two different antibody fragments. This intermediary approach simplifies the production process by enabling modular assembly through hybridization rather than complex chemical coupling, while maintaining the ability to achieve high avidity through proper spacer design
Solution Approach 2:
The bispecific antibody is segmented into modular components: two different antibody fragments (each binding to different epitopes) connected by a nucleic acid spacer. This segmentation allows independent optimization of each binding domain and simplifies production by enabling separate synthesis and assembly of functional modules
2Reliability
If monovalent antibodies with low individual affinity are used to achieve high avidity through cumulative binding, then target tissue binding is improved, but affinity for non-target tissue increases causing cross-reactivity
Solution Approach 1:
The patent changes the physical parameter of distance between binding sites by using nucleic acid spacers of specifically designed lengths (typically 10-50 nucleotides). This parameter control allows optimization of the geometric arrangement to achieve high avidity at target sites while reducing non-specific binding to off-target tissues through proper spatial separation
3Reliability
If recombinant engineering of binders is performed to create bispecific antibodies, then production complexity increases due to purification of heterodimers, but affinity and specificity can be improved
Solution Approach 1:
The patent replaces the mechanical/chemical system of covalent bonding and complex purification with a nucleic acid hybridization system. The antibody fragments are connected through complementary single-stranded DNA or RNA sequences that anneal together, eliminating the need for sophisticated chemical coupling and purification steps while maintaining high binding specificity and affinity
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 enables the creation of a bi-valent binding agent with enhanced specificity and affinity for target antigens, reducing cross-reactivity with non-target tissues and simplifying the production process by using hybridizing nucleic acid sequences and a linker of defined length, thereby improving the avidity and binding efficiency.
Implementation Method 1
A and B is a monovalent binder... capable of binding two different epitopes on one antigen or to two different antigens
Implementation Method 2
S is a spacer of at least 1 nm in length... a':a as well as b:b' is a binding pair wherein a' and a do not interfere with the binding of b to b' and vice versa
Implementation Method 3
a':a as well as b:b' is a binding pair... wherein the sequences of the binding pair a':a do not bind to the sequences of the binding pair b:b'
Data Source
Figure 1a~1d
Figure 2
Figure 3
AI summary
The present invention relates to a binding agent of the FormulaA - a':a - S- b:b' - B:X(n), wherein A as well as B is a monovalent binder, wherein a':a as well as b:b' is a binding pair wherein a' and a do not interfere with the binding of b to b' and vice versa, wherein S is a spacer of at least 1 nm in length, wherein :X denotes a functional moiety bound either covalently or via a binding pair to at least one of a', a, b, b' or S, wherein (n) is an integer and at least 1, wherein - represents a covalent bond, and wherein the linker a - S - b has a length of 6 to 100 nm. Also disclosed are a method of producing such binding agent and certain uses thereof.