CD3/4-1BB Bispecific Antibody Combination for Solid Tumors
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Solution Overview
Problem
Existing CD3 bispecific antibodies face challenges in effectively targeting solid tumors due to physical barriers and immunosuppressive tumor microenvironments, leading to poor clinical efficacy, while B7-H4-targeting antibodies show promise for breast, ovarian, and endometrial cancers with low expression in normal tissues.
Innovation Solution
A bispecific antibody combination comprising a CD3-targeting domain and a tumor-associated antigen (TAA)-targeting domain, along with a 4-1BB-targeting domain and a TAA-targeting domain, specifically targeting B7-H4 or Her2, to provide simultaneous first and second signals for T-cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD3 bispecific antibody is used to target solid tumors, then strong anti-tumor activity is achieved in vitro and in animal experiments, but poor clinical efficacy is observed in human trials
Solution Approach 1:
The patent combines CD3-targeting bispecific antibody with B7-H4-targeting antibody into a combination therapy. The CD3 bispecific antibody provides first signal for T-cell activation, while the B7-H4-targeting antibody provides second signal through CD28 interaction. This merging of two antibody functions resolves the contradiction by adding co-stimulatory signal that enhances T-cell activation and persistence in the tumor microenvironment, thereby improving clinical efficacy while maintaining anti-tumor activity.
Solution Approach 2:
The B7-H4-targeting antibody acts as an intermediary that bridges the gap between CD3 bispecific antibody and T-cell activation. By targeting B7-H4 on tumor cells and engaging CD28 on T cells, it provides the necessary second signal that CD3 bispecific antibody alone cannot provide, thus mediating enhanced T-cell response and improving clinical outcomes in solid tumor treatments.
2Reliability
If CD3 bispecific antibody is used alone, then T cells are activated to kill tumor cells, but T-cell apoptosis occurs due to lack of second signal
Solution Approach 1:
The combination therapy ensures continuous T-cell activation by providing both first signal (CD3 engagement) and second signal (CD28 engagement via B7-H4 targeting). This continuous co-stimulatory signal prevents T-cell exhaustion and apoptosis, maintaining productive T-cell response throughout the treatment course and reducing harmful T-cell depletion.
Solution Approach 2:
The B7-H4-targeting antibody serves as an intermediary that supplies the critical second signal through CD28 interaction. This intermediary function prevents T-cell apoptosis by providing continuous co-stimulatory signal, thereby reducing harmful T-cell depletion while maintaining reliable T-cell activation for tumor killing.
3Reliability
If CD3 bispecific antibody is used in solid tumors with stromal cells and extracellular matrix, then physical barriers block lymphocyte infiltration, but the antibody cannot effectively reach tumor cells
Solution Approach 1:
The B7-H4-targeting antibody acts as an intermediary that facilitates T-cell engagement with tumor cells through the B7-H4/CD28 interaction. This intermediary mechanism provides co-stimulatory signal that enhances T-cell motility and persistence in the tumor microenvironment, helping T cells overcome physical barriers formed by stromal cells and extracellular matrix to effectively reach and kill tumor cells.
Solution Approach 2:
The combination therapy changes the functional parameters of T-cell response by adding co-stimulatory signal. This parameter change enhances T-cell activation, motility, and persistence, enabling T cells to more effectively navigate through physical barriers in solid tumors and reach target cells for killing.
Data Source
AI summary
Provided are a bispecific antibody combination and a use thereof. The bispecific antibody combination comprises a bispecific antibody I and a bispecific antibody II. The bispecific antibody I comprises a CD3-targeting domain and a tumor-associated antigen-targeting domain, and the bispecific antibody II comprises a 4-1BB-targeting domain and a tumor-associated antigen-targeting domain. Further provided are a pharmaceutical composition, a test kit, a kit of parts and an administration device containing the same, and a method of treating cancer by using the same. The concomitant use of the bispecific antibodies not only reduces the exhaustion of T cells, but also significantly facilitates tumor killing at a later stage. Moreover, the concomitant use of the bispecific antibodies, especially when targeting different epitopes of the same tumor-associated antigen or targeting different tumor-associated antigens, produces a strong synergistic killing effect. The use of the bispecific antibody combination and the pharmaceutical composition containing the same provides a potential clinical solution for effectively treating solid tumors.