Bispecific binding molecules that target the tumor microenvironment and an immune checkpoint protein
Inventors
Wang, Jin • RAINEY, Godfrey Jonah
Assignees
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Publication Number
US-11718673-B2
Publication Date
2023-08-08
Expiration Date
Abstract
Bispecific binding proteins that bind IL-1β or IL-1R and a checkpoint protein are provided, together with methods of making the proteins. The checkpoint protein may be PD-1 or PD-L1. The binding proteins may have immunoglobulin-like structures that contain human Fab or scFv domains. A novel bispecific antibody format is provided. Methods of making the binding proteins are provided, together with pharmaceutical compositions containing the proteins. The binding proteins and pharmaceutical compositions may be used for treating or preventing diseases such as cancer.
Core Innovation
The invention provides bispecific immunoglobulin-like binding proteins that target both an immune checkpoint and IL-1β or IL-1R. The binding proteins comprise at least two binding domains configured such that one binding domain specifically binds and inhibits activation of PD-1 or PD-L1 immune checkpoint interaction and another binding domain specifically binds and inhibits the activity of IL-1β.
The binding proteins are described with engineered bispecific antibody architectures, including BiS2, BiS3, FIT-Ig, and FAT-Ig formats, with specified arrangements of immunoglobulin-like structures, domain compositions, and connectivity features. The described architectures include scFv-based binding domain arrangements with VH/VL variable regions, as well as heavier-chain immunoglobulin domains such as CH1, CH2, and CH3, together with hinge regions and disulfide bonds.
The document further describes defined CDR and VH/VL sets for PD-1/PD-L1 binding and for IL-1β binding using multiple SEQ ID numbers for CDR1, CDR2, and CDR3 in the relevant VH and VL domains. In addition, nucleic acids and vectors, protein production approaches, and formulation with pharmaceutically acceptable excipient are described, along with characterization indications using flow cytometry binding and functional reporter/functional assays demonstrating concurrent binding and blockade of PD-1 activity and IL-1β activity compared to control human IgG.
Claims Coverage
The independent claim is directed to a binding protein with two functional binding domains: a first domain that specifically binds and inhibits PD-1 activation and a second domain that specifically binds and inhibits IL-1β activity. The main claim contains inventive features specifying an scFv-based first binding domain on a heavy chain, a second VH/VL pair forming the second binding domain, and defined CDR sets identified by SEQ ID numbers.
Two-domain bispecific binding protein targeting PD-1 and IL-1β
A binding protein comprising a first binding domain and a second binding domain, wherein the first binding domain specifically binds and inhibits activation of PD-1, and wherein the second binding domain specifically binds and inhibits the activity of IL-1β, with the binding protein having specified heavy-chain and light-chain components forming both binding domains.
ScFv-form first binding domain with defined CDRs on heavy chain
A heavy chain comprising, from N- to C-terminus, a single chain Fv comprising a first VH domain and a first VL domain, linked to a second VH domain, where the scFv forms the first binding domain; the first VH domain comprises CDR1 of SEQ ID NO.:7, CDR2 of SEQ ID NO.:8, and CDR3 of SEQ ID NO.:9, and the first VL domain comprises CDR1 of SEQ ID NO.:10, CDR2 of SEQ ID NO.:11, and CDR3 of SEQ ID NO.:12; and the heavy chain further comprises CH1, CH2, and CH3 domains.
Second VH/VL pair forming second binding domain with defined CDRs
A light chain comprising a second VL domain comprising CDR1 of SEQ ID NO.:52, CDR2 of SEQ ID NO.:53, and CDR3 of SEQ ID NO.:54, and including a CL domain; where the second VH domain and the second VL domain form the second binding domain, with the second VH domain comprising CDR1 of SEQ ID NO.:49, CDR2 of SEQ ID NO.:50, and CDR3 of SEQ ID NO.:51.
Overall, the claim coverage focuses on a bispecific binding protein with one PD-1-inhibitory binding domain and one IL-1β-inhibitory binding domain, implemented using an scFv-based first binding domain on a heavy chain with specified CDR SEQ ID numbers, and a second binding domain formed by a defined second VH and second VL pairing with specified CDR SEQ ID numbers.
Stated Advantages
Simultaneous inhibition of PD-1/PD-L1 interaction and IL-1β/IL-1R activity.
Concurrent binding demonstrated by flow cytometry sandwich binding to cell-surface PD-1 and soluble IL-1β, with higher mean fluorescence than control IgG.
Functional blockade demonstrated by reporter/functional assays showing blockade of PD-1 activity and IL-1β activity with substantially higher activity than control human IgG.
Documented Applications
Cancer treatment and prevention by administering the described binding proteins to a subject in need.
A pharmaceutical composition including the binding protein together with a pharmaceutically acceptable excipient.
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