Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10836833-B2
Publication Date
2020-11-17
Expiration Date
Abstract
The present disclosure is broadly concerned with the field of cancer immunotherapy. For example, the present disclosure generally related to a binding molecule comprising antibody variable light (VL) regions, variable heavy (VH) regions, constant heavy 1 (CH1) regions, and light chain constant (CL) regions that are configured to form two antigen binding Fab regions and an antigen binding Fv region so that the binding molecule binds to two different antigens.
Core Innovation
The invention relates to antibody like cell engagers (ALiCE), which are multivalent cell-engaging binding molecules composed of antibody-derived polypeptides that assemble into two antigen-binding Fab regions and one antigen-binding Fv region. The binding molecule does not comprise a CH2 domain or a CH3 domain, and the Fab regions are formed from VH and CH1 components with light chain components to provide Fab antigen binding.
The Fv region is formed by a VH region and a VL region, enabling binding to Cluster of Differentiation (CD) 3. In this format, the first Fab region and the second Fab region bind to a cancer antigen, while the Fv region binds CD3. The cancer antigen includes PD-L1, CD19, CD20, EGFR, and Her2, and may also be characterized as a TAA or TSA.
The disclosure also describes structural and functional rationale for VH-VL heterodimerization efficiency and expected immunological synaptic distance, and contrasts the format with BiTE, DART, and ScFv formats by stating expected improved stability. Optional features include hinge region selection from IgG1, IgG2, IgG3, or IgG4, flexible peptide linkers such as G4S repeats, and albumin-binding domain or site for half-life extension.
Claims Coverage
The independent claim set covers one ALiCE binding molecule with two Fab regions and one Fv region, while lacking CH2 and CH3 domains. The claims define how these regions are assembled from antibody-derived polypeptides and specify that the Fab regions bind a cancer antigen and the Fv region binds CD3.
Two Fab regions and an Fv region binding format
A binding molecule comprising a first antigen binding Fab region, a second antigen binding Fab region, and an antigen binding Fv region, wherein the first Fab region and the second Fab region bind to a cancer antigen and the Fv region binds to Cluster of Differentiation (CD) 3.
Fab region construction from VH and CH1 with light chain
The first polypeptide and the first VH region and the first CH1 region form a first antigen binding Fab region; the second polypeptide and the third VH region and the second CH1 region form a second antigen binding Fab region.
Fv region construction from VH and VL
The second VH region of the third polypeptide and the VL region of the fourth polypeptide form an antigen binding Fv region.
CH2 and CH3 domain absence
The binding molecule does not comprise a CH2 domain or a CH3 domain.
Cancer antigen selection as PD-L1
The binding molecule wherein the cancer antigen is Programmed Death-Ligand 1 (PD-L1).
Cancer antigen selection as CD19
The binding molecule wherein the cancer antigen is CD19.
Hinge selection from IgG hinge subtypes
The binding molecule uses an antibody hinge region that is an IgG hinge region selected from IgG1, IgG2, IgG3, or IgG4.
Linker including one or more repeats of G4S (GGGGS)
The binding molecule wherein the linker includes one or more repeats of the amino acid sequence GGGGS (G4S) (SEQ ID NO: 130).
Overall, the claim coverage centers on an ALiCE binding molecule that lacks CH2 and CH3 and is constructed from antibody-derived polypeptides to generate two Fab antigen-binding regions for a cancer antigen together with an Fv region that targets CD3. Dependent claims further specify particular cancer antigens, hinge subtype options, and linker composition.
Stated Advantages
Expected improved stability versus BiTE, DART, and ScFv formats.
Reduced target-independent T-cell activation due to monovalent/low-affinity Fv binding.
Reduces undesirable Fc-mediated cytotoxicity due to lacking or altering CH2/CH3 Fc-related regions.
Improves heterodimerization via VH–VL native interaction.
Improves PK stability relative to BiTE/DART formats.
Reduced toxicity markers versus BiTE.
Documented Applications
Redirection/engagement of immune cells via CD3 binding with cancer antigen binding by the two Fab regions, including T-cell subsets (e.g., CD8+ T, CD4+ T, T helper, Treg, cytotoxic T).
Targeting cancer antigens including PD-L1, CD19, CD20, EGFR, and Her2 using the Fab-region binding while engaging CD3 through the Fv region.
T cell redirecting for T cell activation and T cell cytotoxicity via binding to CD3 using the Fv region while binding a cancer antigen via the Fab regions.
Binding molecule examples targeting PD-L1×CD3, including example constructs such as ACE-05, are described.
T-cell redirecting and cytotoxicity outcomes, including in vitro and in vivo efficacy comparisons with xenograft tumor regression.
Binding and functional characterization of constructs including ACE-05 and ACE-09 using ELISA and kinetics measurements.
Interested in licensing this patent?