Tetravalent Multispecific Binding Molecules for Low-Density Tumor Antigens
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Solution Overview
Problem
Existing multispecific antigen-binding molecules face challenges in targeting low-density tumor antigens with high specificity and efficacy, leading to potential toxicity due to expression on normal cells and low antigen density.
Innovation Solution
Multispecific binding molecules (MBMs) comprising two polypeptides with antigen binding domains, dimerization moieties, and Fab portions, configured to enhance T cell activation and reduce immunogenicity, even when targeting low-density antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional multispecific antibodies are used to target tumor-associated antigens, then T cell activation can be achieved, but toxicity occurs due to expression of TAAs on normal cells as well as tumor cells
Solution Approach 1:
The antibody is divided into separate functional domains: a T cell targeting moiety (anti-CD3) and a tumor antigen targeting moiety. These are connected via a linker to form a multispecific antibody that can simultaneously engage both T cells and tumor cells, enabling targeted activation while reducing off-target effects
Solution Approach 2:
The multispecific antibody acts as an intermediary molecule that bridges T cells and tumor cells. By containing both T cell antigen (TCA) targeting moieties and tumor antigen targeting moieties, it mediates the interaction between these two cell types, enabling selective T cell activation at the tumor site while minimizing activation of T cells against normal cells expressing TAAs
2Reliability
If tumor-specific antigens are used as targets, then high specificity can be achieved, but low antigen density on cancer cells reduces targeting efficacy
Solution Approach 1:
The antibody combines multiple functional elements into a single molecule: T cell targeting moieties, tumor antigen targeting moieties, and a linker. This merged structure allows simultaneous engagement of T cells and low-density tumor antigens, compensating for low antigen density through multivalent binding and enhanced local concentration of effector functions
Solution Approach 2:
The multispecific antibody performs multiple functions simultaneously: it targets T cells via anti-CD3 moieties, targets tumor cells via tumor antigen moieties, and facilitates their interaction. This multi-functionality enables effective targeting even when individual antigen densities are low, as the combined effect of multiple binding interactions compensates for low copy numbers
3Productivity
If multisspecific antibody formats are designed to enhance T cell activation, then immune response efficacy improves, but immunogenicity increases
Solution Approach 1:
The patent optimizes parameters including the linker sequence composition and length, the specific antibody sequences used for T cell and tumor antigen targeting, and the overall molecular structure. These parameter optimizations balance immunogenicity and efficacy by selecting sequences that maintain functional activity while minimizing immune recognition of the therapeutic molecule itself
Data Source
AI summary
The present disclosure relates to multispecific binding molecules comprising a polypeptide chain comprising, in N- to C-terminal orientation, an antigen binding domain (e.g., an scFv, a sdAb), a dimerization moiety (e.g., an Fc domain), and a Fab component (e.g., VH or VL). Certain aspects relate to multimeric molecules comprising two polypeptide chains, each comprising, in N- to C-terminal orientation, an antigen binding domain (e.g., an scFv, a sdAb), a dimerization moiety (e.g., an Fc domain), and a Fab component (e.g., VH or VL). The multispecific binding molecules may further comprise one or more additional polypeptide chains associated with the Fab component to form a Fab. The disclosure further provides pharmaceutical compositions comprising the multispecific binding molecules, and methods of use of the multispecific binding molecules in antigen-specific immune activation and in therapeutic applications, as well as nucleic acids encoding the multispecific binding molecules, recombinant cells that express the multispecific binding molecules, and methods of producing the multispecific binding molecules.