BTLA Antibodies and Uses Thereof

Abstract

The invention relates to BTLA antibodies that block BTLA-HVEM interaction and uses thereof.

Description

FIELD OF THE INVENTION[0001]The invention relates to BTLA antibodies that blocks BTLA-HVEM interaction and uses thereof.BACKGROUND OF THE INVENTION[0002]Co-receptor signalling is an important mechanism for coordinating and tightly regulating immune responses. The usual scheme of activation of αβ T cells relies on positive signals given by peptide antigens presented by HLA class I or II. Co-receptor signals will either increase or prevent this activation.Among the negative signalling molecules, those belonging to CD28 / B7 families are by far the most studied. Three members of this family have been described: CTL-associated antigen-4 (CTLA-4), programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA). They all play a role in the control of tolerance. They provide negative signals that limit, terminate and / or attenuate immune responses.[0003]BTLA (CD272) is the most recently described member of the CD28 family, it was first identified as a transcript highly specific to T helper...

AI Technical Summary

Benefits of technology

[0032]The inventors have demonstrated that a BTLA antibody that blocks BTLA-HVEM interaction may be used to overcome the immunosuppressive mechanisms mediated by HVEM observed in cancer patients and during chronic infections.

[0071]Amino acid sequence modification(s) of the antibodies described herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. It is known that when a humanized antibody is produced by simply grafting only CDRs in VH and VL of an antibody derived from a non-human animal in FRs of the VH and VL of a human antibody, the antigen binding activity is reduced in comparison with that of the original antibody derived from a non-human animal. It is considered that several amino acid residues of the VH and VL of the non-human antibody, not only in CDRs but also in FRs, are directly or indirectly associated with the antigen binding activity. Hence, substitution of these amino acid residues with different amino acid residues derived from FRs of the VH and VL of the human antibody would reduce of the binding activity. In order to resolve the problem, in antibodies grafted with human CDR, attempts have to be made to identify, among amino acid sequences of the FR of the VH and VL of human antibodies, an amino acid residue which is directly associated with binding to the antibody, or which interacts with an amino acid residue of CDR, or which maintains the three-dimensional structure of the antibody and which is directly associated with binding to the antigen. The reduced antigen binding activity could be increased by replacing the identified amino acids with amino acid residues of the original antibody derived from a non-human animal.

[0086]It may be also desirable to modify the antibody of the invention with respect to effector function, e.g. so as to enhance antigen-dependent cell-mediated cytotoxicity (ADCC) and / or complement dependent cytotoxicity (CDC) of the antibody. This may be achieved by introducing one or more amino acid substitutions in an Fc region of the antibody. Alternatively or additionally, cysteine residue(s) may be introduced in the Fc region, thereby allowing inter-chain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and / or increased complement-mediated cell killing and / or antibody-dependent cellular cytotoxicity (ADCC) (Caron PC. et al. J Exp Med. 1992 Oct. 1;176(4):1191-5 and Shopes B. J Immunol. 1992 May 1;148(9):2918-22).Therapeutic Uses of the Antibodies of the Invention

[0117]The preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.

[0123]Nanocapsules can generally entrap compounds in a stable and reproducible way. To avoid side effects due to intracellular polymeric overloading, such ultrafine particles (sized around 0.1 μm) are generally designed using polymers able to be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles that meet these requirements are contemplated for use in the present invention, and such particles may be are easily made.

Problems solved by technology

To date, no satisfactory approach has been proven to induce potent immune responses against vaccines, especially in cancer patients.

Methods have yet to be devised to overcome the immunosuppressive mechanisms observed in cancer patients, and during chronic infections.

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