Antibody therapies for human immunodeficiency virus (HIV)
Inventors
Barouch, Dan H. • Kerwin, Bruce A. • Ketchem, Randal R. • Gillespie, Alison J. • Siska, Christine C. • Clark, Rutilio H. • Floyd, Julee A. • Shaver, Jeremy M. • Rogers, Richard S.
Assignees
Beth Israel Deaconess Medical Center Inc • Just Evotec Biologics Inc
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Publication Number
US-11845788-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Featured are PGT121 variant antibodies or fragments thereof, which can be administered, e.g., as antibody therapies for treating human immunodeficiency virus (HIV) infection. In particular, featured are methods of treating subjects infected with HIV and/or blocking HIV infections in subjects at risk of HIV transmission using the PGT121 variant antibodies or fragments thereof.
Core Innovation
The invention relates to an antibody or antigen-binding fragment thereof comprising a heavy chain variable domain and a light chain variable domain for PGT121. The heavy chain variable domain includes HC-CDR1, HC-CDR2, and HC-CDR3 amino acid sequences corresponding to SEQ ID NO: 1244, SEQ ID NO: 1246, and SEQ ID NO: 1248, and has at least 90% sequence identity to SEQ ID NO: 1393, with the 90% identity occurring within a framework (FR) region. The heavy chain variable domain includes at least one mutation selected from A27G, D31E, D31S, Q40P, D56E, D56S, N68T, V78F, S81K, V83S, A84S, K92V, and N124Q.
The light chain variable domain includes LC-CDR1, LC-CDR2, and LC-CDR3 amino acid sequences corresponding to SEQ ID NO: 1236, SEQ ID NO: 1238, and SEQ ID NO: 1240, and has at least 90% sequence identity to SEQ ID NO: 1394, with the 90% identity occurring within a framework (FR) region. The light chain variable domain includes at least one mutation selected from S1P, D2S, E9Q, S37V, P58S, P61G, S72G, D87E, and T101K.
The disclosed PGT121 variant antibodies and fragments are defined through combinations of heavy- and light-chain CDR amino-acid sequences together with corresponding framework region changes and defined variable-domain residue ranges. The document links variants to stability and solubility optimization while retaining HIV neutralization against selected pseudoviruses.
The described variants are disclosed as maintaining viral neutralization while improving biophysical properties, including increased solubility, increased low-pH stability, increased thermal stability, and increased chemical stability against guanidine hydrochloride (GuHCl). The improved properties are linked to manufacturability and storage stability.
Claims Coverage
The disclosure includes one independent claim directed to an antibody or antigen-binding fragment with specified heavy- and light-chain variable domain sequence identity criteria, defined CDR sequences, and framework mutations. Two inventive feature sets are identified, one for the heavy chain and one for the light chain.
Framework-region constrained heavy-chain variable domain with specified CDRs and mutations
An antibody or antigen-binding fragment thereof comprising a heavy chain variable domain with at least 90% sequence identity to SEQ ID NO: 1393, wherein the heavy chain variable domain comprises HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1244, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 1246, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 1248; and wherein the heavy chain variable domain includes at least one of the following mutations: A27G, D31E, D31S, Q40P, D56E, D56S, N68T, V78F, S81K, V83S, A84S, K92V, and N124Q; with the at least 90% sequence identity occurring within a framework (FR) region.
Framework-region constrained light-chain variable domain with specified CDRs and mutations
An antibody or antigen-binding fragment thereof comprising a light chain variable domain with at least 90% sequence identity to SEQ ID NO: 1394, wherein the light chain variable domain comprises LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1236, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 1238, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 1240; and wherein the light chain variable domain includes at least one of the following mutations: S1P, D2S, E9Q, S37V, P58S, P61G, S72G, D87E, and T101K; with the at least 90% sequence identity occurring within a framework (FR) region.
Claim coverage centers on antibodies or antigen-binding fragments having framework-region sequence identity to SEQ ID NO: 1393 and SEQ ID NO: 1394 while preserving defined heavy- and light-chain CDR sequences and including specified framework point mutations.
Stated Advantages
Maintains viral neutralization while improving biophysical properties.
Increased solubility.
Increased low-pH stability.
Increased thermal stability.
Increased chemical stability against guanidine hydrochloride (GuHCl).
Improved properties are linked to manufacturability and storage stability.
Documented Applications
Administration of antibody compositions for blocking HIV infection and/or reducing proviral DNA and plasma viral load.
Use in combination with immunomodulators, antiretroviral agents (ARVs), and broadly neutralizing antibodies (bnAbs).
Neutralization of HIV pseudoviruses.
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