Bispecific CD16A Binders That Prevent NK Cell CD16A Shedding
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Solution Overview
Problem
Existing bispecific antibody constructs for activating natural killer (NK) cells to target cancer cells face challenges due to CD16A shedding upon activation, leading to impaired ADCC efficacy and limited cytotoxic activity.
Innovation Solution
Development of a bispecific antibody construct with a high-affinity anti-CD16A binding domain that stabilizes CD16A expression on NK cells, preventing shedding and maintaining long-lasting activation, thereby enhancing cytotoxic activity against cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If bisspecific antibody constructs are used to activate NK cells for tumor cell lysis, then cytotoxic activity is enhanced, but CD16A shedding occurs leading to impaired ADCC efficacy
Solution Approach 1:
The patent applies parameter changes by engineering the antibody construct to have high affinity binding to CD16A, specifically optimizing the binding characteristics to prevent shedding while maintaining activation. The high-affinity binding parameter is deliberately set to overcome the shedding phenomenon that occurs with conventional constructs.
Solution Approach 2:
The patent implements preliminary action by designing the antibody construct with pre-optimized high-affinity binding properties before administration. The construct is engineered in advance to stabilize CD16A expression and prevent shedding, rather than attempting to address shedding after it occurs.
2Productivity
If CD16A activation is induced for NK cell proliferation and memory-like cytotoxicity, then anti-tumor activity is improved, but CD16A down-regulation limits sustained activity
Solution Approach 1:
The patent changes the binding affinity parameter of the antibody construct to high affinity, which fundamentally alters the duration of CD16A engagement. This high-affinity binding prevents the typical down-regulation and shedding kinetics, thereby extending the duration of NK cell activation and cytotoxic activity.
Solution Approach 2:
The patent achieves continuity of useful action by designing the antibody construct to maintain stable CD16A expression on NK cells over time. The high-affinity binding ensures continuous engagement and activation, preventing the interruption that would normally occur through shedding and down-regulation.
3Reliability
If high-affinity anti-CD16A binding is implemented, then CD16A expression is stabilized and shedding is prevented, but construct complexity increases
Solution Approach 1:
The patent applies parameter changes by optimizing the antibody sequence to achieve high affinity binding through specific amino acid modifications in the CDR regions. This sequence optimization achieves the desired stability without requiring complex structural modifications or additional components.
Solution Approach 2:
The patent employs composite material principles by combining the anti-CD16A variable domain with a tumor antigen-binding domain in a bispecific construct. This composite approach achieves multiple functions (stabilizing CD16A and targeting tumors) in a single integrated molecule, rather than requiring separate components.
Data Source
AI summary
The present invention relates to a bispecific antibody construct comprising (a) a first binding domain (A), which is capable of specifically binding to a first target (A′) that is CD16A on the surface of an immune effector cell, wherein the first binding domain comprises: (i) a VL region comprising CDR-L1 as depicted in SEQ ID NO: 4, a CDR-L2 as depicted in SEQ ID NO: 5, and a CDR-L3 as depicted in SEQ ID NO: 6; and (ii) a VH region as depicted in SEQ ID NO: 7 or SEQ ID NO: 134; and (b) a second binding domain (B), which is capable of specifically binding to a second target (B′) that is an antigen on the surface of a target cell. The present invention also relates to related nucleic acid molecules, vectors, host cells, methods of producing the antibody constructs, pharmaceutical compositions, medical uses, and kits.