Antigen binding molecules targeting SARS-CoV-2
Inventors
Borriello, Francesco • Ramos, Alexis Hiram
Assignees
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Publication Number
US-11993644-B2
Publication Date
2024-05-28
Expiration Date
Abstract
The disclosure provides, in various embodiments, polypeptides (e.g., antibodies and antigen binding fragments thereof) that specifically bind to S2 domains of betacoronavirus Spike glycoproteins, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoproteins. The disclosure also provides, in various embodiments, fusion proteins comprising one or more of polypeptides, polynucleotides encoding polypeptides, vectors and host cells suitable for expressing polypeptides, and methods for treating viral infections (e.g., COVID-19).
Core Innovation
The invention is directed to engineered polypeptides, including antibodies and antigen-binding fragments, that specifically bind a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike). The polypeptides target a conserved S2 domain epitope of SARS-CoV-2 Spike and are defined by heavy-chain and light-chain complementarity-determining regions (CDRs) with specified amino acid sequences.
The invention further defines antibody paratopes and variable-domain features using heavy-chain variable domain (V_H) and light-chain variable domain (V_L) CDRs, including alternative CDR substitution constructs and rules describing CDR similarity and paratope similarity. Additional embodiments include humanized heavy-chain and/or light-chain variable domains, human framework regions, different antibody formats, and fusion proteins.
The disclosed constructs also include polynucleotides, vectors, and host cells expressing the polypeptides. Functional performance targets are described in terms of binding affinity, competition with a reference antibody, neutralization, reduction of infectivity, and developability/self-association characterization, with therapeutic administration and combination-therapy contexts.
Claims Coverage
The independent claims cover SARS-CoV-2 Spike-binding antibody or antigen-binding fragment polypeptides defined by specified heavy-chain and light-chain complementarity-determining regions, totaling six inventive CDR sequence constraints across the heavy and light chains. Additional claim coverage includes humanization, antigen-binding fragment formats, constant-domain features, and therapeutic-use combinations.
SARS-CoV-2 spike-binding antibody polypeptide with specified heavy-chain CDR sequences
A polypeptide that specifically binds SARS-CoV-2-Spike comprising a heavy chain variable domain (V_H) with HCDR1 comprising the amino acid sequence of SEQ ID NO:77, HCDR2 comprising the amino acid sequence of SEQ ID NO:80, and HCDR3 comprising the amino acid sequence of SEQ ID NO:91, wherein the polypeptide is an antibody or an antigen-binding fragment thereof.
SARS-CoV-2 spike-binding antibody polypeptide with specified light-chain CDR sequences
A polypeptide that specifically binds SARS-CoV-2-Spike comprising a light chain variable domain (V_L) with LCDR1 comprising the amino acid sequence of SEQ ID NO:133, LCDR2 comprising the amino acid sequence of SEQ ID NO:141, and LCDR3 comprising the amino acid sequence of SEQ ID NO:144, wherein the polypeptide is an antibody or an antigen-binding fragment thereof.
Humanization and human framework regions for variable domains
A polypeptide comprising a humanized heavy-chain variable domain and/or a humanized light-chain variable domain, with each domain containing human framework regions or a combination thereof.
Antigen-binding fragment formats
The polypeptide is an antigen-binding fragment of an antibody, comprising a single-chain fragment variable (scFv) or a Fab, Fab′, or F(ab′)2 fragment.
Heavy-chain constant domain selection and/or enhancement
The polypeptide includes an antibody heavy chain constant domain having the amino acid sequence of SEQ ID NO:194 and/or includes one or more mutations in the heavy chain constant domain that increase the antibody (or its antigen-binding fragment) serum half-life in humans.
Combination therapy co-selection including vaccine types
A method of treating/reducing infectivity embodiments where a SARS-CoV-2 Spike-binding antibody is selected together with at least one from an antiviral agent, an ACE2 inhibitor, an antibiotic, an antimalarial agent, and a vaccine, including combinations and where the vaccine is selected as either a nucleic acid vaccine or an inactivated virus vaccine.
Claim coverage centers on SARS-CoV-2 Spike-binding antibodies or antigen-binding fragments defined by explicit heavy-chain and light-chain CDR sequences. The claim set further includes humanization and human framework regions, defined antigen-binding fragment classes, heavy-chain constant-domain features, and therapeutic-use embodiments with combination therapy co-selection.
Stated Advantages
Improved neutralization potency/efficacy versus a Reference Antibody and sotrovimab in pseudovirus assays.
Protection from weight loss and reduced lung weights in hamster models for Delta and Omicron BA.2.
AB-1 does not enhance infection in FcγR-expressing cells.
Binding affinity metrics, competition with a reference antibody, neutralization metrics, and infectivity reduction are described.
Developability and self-association are characterized using AC-SINS.
Documented Applications
Neutralization and efficacy evaluation of human IgG1 anti-S2 stem-helix antibodies AB-1, AB-15, and AB-17 against SARS-CoV-2 variants, including pseudovirus and live-virus hamster model contexts.
Resistance characterization against epitope polymorphisms and evaluation of combination benefit with class 3/class 4 anti-RBD monoclonal antibodies.
ADE testing in FcγR-expressing cells using THP-1, U-937, and PBMCs.
Pharmaceutical composition and combination-therapy contexts are described.
Therapeutic administration intended to reduce infectivity and neutralize SARS-CoV-2 variants is described.
Polynucleotides, vectors, and host cells are included for expression.
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