Multispecific antibodies targeting human immunodeficiency virus and methods of using the same
Inventors
Guenaga, Javier • Li, Yuxing • Steinhardt, James • Mascola, John R.
Assignees
International AIDS Vaccine Initiative Inc • University of Maryland College Park • US Department of Health and Human Services
Publication Number
US-11149082-B2
Publication Date
2021-10-19
Expiration Date
2037-10-17
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present disclosure relates to multispecific antibodies targeting the human immunodeficiency virus-1 (HIV-1) envelope, methods for their production, pharmaceutical compositions containing said antibodies and uses thereof in treatment and prevention of HIV infection.
Core Innovation
The invention relates to multispecific antibodies targeting the human immunodeficiency virus-1 (HIV-1) envelope protein (Env), methods for their production, pharmaceutical compositions including such antibodies, and their use for treatment and prevention of HIV infection. These multispecific antibodies comprise antigen-binding fragments derived from at least two different antibodies that bind non-overlapping epitopes on the HIV-1 Env protein. The variable heavy (VH) domain from one antibody light chain and the variable light (VL) domain from the other antibody light chain are connected by one or more tetra-glycine serine (G4S) protein linkers.
The problem addressed is the limited efficacy of existing broad neutralizing antibodies (bNAbs) against HIV-1, due to the virus's extensive antigenic diversity and rapid development of resistance mutations against single bNAb therapies. Although antibody cocktails exhibit improved efficacy, manufacturing complexity and steric constraints in traditional bispecific formats limit their use. There is a need for multispecific single-agent antibodies capable of simultaneously targeting multiple conserved epitopes to enhance avidity, breadth, and potency of neutralization.
The invention provides a structure-based rational design approach to generate multispecific (including bi-, tri-, tetra-, and pentaspecific) antibodies that link variable domains of distinct bNAbs via flexible G4S linkers to enable inter-protomer crosslinking of multiple epitopes within the HIV-1 Env trimer. This design overcomes steric hindrance and rigidity limitations of prior bispecific formats. The optimized multispecific antibodies show exceptional neutralization breadth and potency against diverse HIV-1 isolates, including strains resistant to parental bNAbs, and provide a platform for next-generation HIV therapies and prophylactics.
Claims Coverage
The patent contains 18 claims with multiple inventive features focused on multispecific antibodies targeting HIV-1 Env. The main inventive features relate to the antibody compositions, linker configurations, epitope specificities, molecular architectures, and methods of use and production.
Multispecific antibody comprising linked variable domains from two antibodies binding non-overlapping HIV-1 Env epitopes
An antibody or antigen-binding fragment with a first light chain and heavy chain and a second light chain and heavy chain, each derived from distinct antibodies or fragments. The antibodies bind non-overlapping epitopes of HIV-1 Env. The VH of one light chain and VL of the other are connected by one or more linkers.
Use of tetra-glycine serine (G4S) protein linkers to connect variable domains
The linkers connecting VH and VL domains comprise two or more tetra-glycine serine (G4S) peptide linkers. The linker excludes short glycine or serine sequences of specified types, enabling flexible and effective inter-domain connection to facilitate multispecific antibody function.
Targeting conserved HIV-1 env epitopes for multispecific binding
The antibodies specifically bind non-overlapping epitopes located among the CD4-binding site, V1/V2-glycan region, V3-glycan region, gp41 membrane proximal external region (MPER), or the gp120/gp41 interface of HIV-1 envelope protein.
Incorporation of third or more antibodies for tri- or multi-specific antibodies
Multispecific antibodies comprising three or four antibodies binding distinct non-overlapping epitopes are disclosed. Such multispecific antibodies use combinations of variable domain linkages and Fc region engineering to achieve enhanced potency and breadth.
Antibody variable domain sequences and CDR compositions
The variable heavy and light chain domains of the antibodies comprise specific complementarity determining regions (CDRs) as recited in the sequences SEQ ID NOs 2, 6, 10, 14, 19, 31, 35, 39, 43, and others, and include variants with at least 95% sequence identity to enable broad and potent neutralization.
Pharmaceutical compositions and methods of treating HIV infection
Methods of treating or preventing HIV infection involve administering the effective amount of the multispecific antibody or composition thereof. Pharmaceutical formulations containing these antibodies, nucleic acids encoding them, expression vectors, host cells, and immunoconjugates coupled to cytotoxic agents are also claimed.
The claims cover multispecific antibodies targeting multiple conserved HIV-1 Env epitopes linked by specific tetra-glycine serine linkers, including bi- and tri-specific formats with defined variable domain sequences, compositions comprising these antibodies, and methods of using and producing them for HIV infection treatment and prevention.
Stated Advantages
Multispecific antibodies display superior avidity, potency, and neutralization breadth against diverse HIV-1 isolates relative to individual parental antibodies or empirical antibody combinations.
Rational design of bispecific and trispecific antibodies enables simultaneous multi-epitope engagement, overcoming steric constraints of prior formats and allowing crosslinking of adjacent Env protomers.
Multispecific antibodies can neutralize virus strains resistant to individual bNAbs, reducing the likelihood of viral escape and resistance development.
Single-agent multispecific antibodies are desirable from manufacturing and regulatory standpoints compared to antibody cocktails.
Modified Fc regions in multispecific antibodies can improve in vivo stability, effector functions such as antibody-dependent cell cytotoxicity, serum half-life, and mucosal localization.
Documented Applications
Prevention and treatment of HIV infection in subjects in need thereof by administration of an effective amount of the multispecific antibodies or pharmaceutical compositions.
Use in studies aimed at preventing HIV disease progression, mother to child transmission of HIV, achieving HIV remission, and potentially curing HIV infection.
Production methods involving recombinant expression of nucleic acids encoding multispecific antibodies in host cells, subsequent recovery and purification for pharmaceutical use.
Immunoconjugates comprising multispecific antibodies coupled to cytotoxic agents for targeted killing of HIV-infected cells.
Interested in licensing this patent?