Invented by Michael Molloy, Jay Rothstein, Dov PECHENICK, Linda Snyder, Gordon Powers, Janssen Pharmaceuticals Inc, Immunext Inc

The market for Anti-human VISTA antibodies, and their use In recent years, there has been a growing interest in the development and use of anti-human VISTA antibodies. V-domain Ig suppressor of T cell activation (VISTA) is a protein that plays a crucial role in regulating immune responses. It is primarily expressed on immune cells such as T cells, dendritic cells, and myeloid-derived suppressor cells. The discovery of VISTA as an immune checkpoint molecule has opened up new avenues for cancer immunotherapy. Immune checkpoint inhibitors have revolutionized the treatment of various cancers by unleashing the body’s immune system to attack cancer cells. Antibodies targeting immune checkpoints such as PD-1 and CTLA-4 have shown remarkable success in clinical trials and have been approved for the treatment of several types of cancer. Anti-human VISTA antibodies are designed to block the interaction between VISTA and its receptors, thereby enhancing the anti-tumor immune response. These antibodies can potentially overcome the immunosuppressive effects of VISTA, leading to increased activation and proliferation of T cells, improved tumor infiltration, and enhanced tumor cell killing. The market for anti-human VISTA antibodies is expected to witness significant growth in the coming years. The increasing prevalence of cancer and the need for more effective treatment options are driving the demand for novel immunotherapies. The success of immune checkpoint inhibitors targeting PD-1 and CTLA-4 has created a favorable environment for the development of antibodies targeting other immune checkpoints, including VISTA. Several pharmaceutical companies and biotechnology firms are actively involved in the development of anti-human VISTA antibodies. These companies are conducting preclinical and clinical trials to evaluate the safety and efficacy of these antibodies in various cancer types. The results from early-phase clinical trials have shown promising outcomes, further fueling the interest in this field. The use of anti-human VISTA antibodies extends beyond cancer immunotherapy. VISTA has also been implicated in the regulation of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Therefore, these antibodies hold potential for the treatment of various autoimmune disorders by modulating the immune response. However, there are challenges associated with the development and use of anti-human VISTA antibodies. One of the major hurdles is the identification of suitable biomarkers to predict patient response. Biomarkers can help identify patients who are more likely to benefit from VISTA-targeted therapies, enabling personalized treatment strategies. Another challenge is the potential for immune-related adverse events (irAEs). As with other immune checkpoint inhibitors, the use of anti-human VISTA antibodies may lead to immune-related toxicities, including inflammation of vital organs. Close monitoring and management of these adverse events are crucial to ensure patient safety. In conclusion, the market for anti-human VISTA antibodies is rapidly expanding, driven by the need for more effective cancer immunotherapies. These antibodies have the potential to enhance the anti-tumor immune response by blocking the immunosuppressive effects of VISTA. Ongoing research and clinical trials will further elucidate the safety and efficacy of these antibodies, paving the way for their potential approval and widespread use in the treatment of cancer and autoimmune diseases.

The Janssen Pharmaceuticals Inc, Immunext Inc invention works as follows

The invention provides anti-human VISTA antibody and fragments that are antagonistic and agonistic. These antagonist antibodies or antibody fragments can be used to block VISTA?s suppressive effects on the T cell immune system and thereby promote immunity. These agonist antibody and fragments can be used to mimic or potentiate VISTA’s suppressive effect on T-cell immunity, and thereby suppress it. These antagonist antibodies are particularly useful for the treatment of infectious diseases and cancer. These agonist antibody fragments and antibodies are particularly useful for the treatment of autoimmunity and allergy, inflammatory and GVHD conditions, sepsis, and transplant recipients. These agonists can also be identified using screening assays.

Background for Anti-human VISTA antibodies, and their use

Immune-negative checkpoint regulator (NCR), pathways have proved to be extraordinary targets in the treatment human immune-related disease. The use of monoclonal antibody (mAb) blocking two NCRs, CTLA-4, and PD-1 to boost tumor immunity has revolutionized the treatment of cancer, and established these pathways in clinically validated targets for human disease. “Also, soluble versions NCR ligands which trigger NCR pathways are being used as immunosuppressive agents to treat autoimmunity. (i.e. AMP-110/B7H4-Ig).

VISTA” (see Ref1) is an NCR ligand whose closest phylogenetic relation is PD LI. VISTA shares homology with PD-LI, but exhibits a unique pattern of expression that is limited to the hematopoietic system. VISTA is highly expressed and constitutively expressed on CDIIbhlgh cells and at a lower level on CD4+, CD8+, and CD4+ T cells. VISTA, like PDLI, is a ligand which profoundly suppresses immune responses (Ref 1) and, similar to PDLI, blocking VISTA can allow for therapeutic immunity against cancer in preclinical oncology model (see Reference 2). While blocking VISTA increases immunity, particularly CD8+ and CD4+ mediated immunity, treatment with a soluble Ig fusion of the extracellular region of VISTA, (VISTA-Ig), suppresses immunity. This has been shown in multiple murine models for autoimmune disease.

Clear evidence has demonstrated that VISTA induces profound suppression of T cells. Dartmouth College, Jannsen and other groups have reported a number of antagonistic antihuman VISTA antibody. These antibodies can be used to treat conditions such as cancer or infection where the immunosuppressive effect of VISTA is wanted. To the best of the inventors? knowledge, no anti-human VISTA antibodies or antibody fragments have been identified that agonize the effects of human VISTA. These agonistic antihuman VISTA antibody and fragments are desirable for treating conditions in which the suppression of immunity (particularly T cell immunity) is desired, and/or where VISTA expression has been aberrantly downregulated.

The invention aims to provide novel anti-human VISTA antibody fragments and antibodies that specifically bind human VISTA, and variants of it, e.g. chimeric, humanized, humanized, or multispecific antihuman VISTA antibodies, which bind human VISTA, and promote or mimic its effects on immunity.

The invention aims to provide an agonistic antigen or fragment of antigen antibody that binds specifically to human VISTA, wherein said agonistic antigen or fragment binds the same or overlapping VISTA epitopes as any of the antihuman VISTA antibody having the CDR with variable heavy and lightweight polypeptides (shown in FIG. 4A-4JJ.

The invention aims to provide an isolated antigen-binding region of human V-domain IgSuppressor of Cell Activation (human VISTA), which inhibits or enhances the immune effects of VISTA, e.g. containing a constant human IgG2 or a Fc region of human IgG2, optionally with the constant human IgG2 or the Fc area binding to the Fc gamma a receptors, such as human CD32A,

The invention aims to provide an agonistic antigen-binding region or fragment of antibody that binds specifically to human VISTA, wherein the agonistic antigen-binding region or fragment binds a VISTA overlapping or including the epitope bound to by any antihuman VISTA antibody having the sequences shown in FIG. 4A-4JJ.

It is a specific object of the invention to provide agonistic antibody or antibody fragment thereof comprising an antigen binding region that specifically binds to human VISTA wherein the agonistic antibody or antibody fragment binds or interacts with one of more residues of an epitope comprising residues of LLDSGLYCCLVVEIRHHHSEHRVH.

It is a specific object of the invention to provide agonistic antibody or antibody fragment thereof comprising an antigen binding region that specifically binds to human VISTA wherein the agonistic antibody or antibody fragment binds or interacts with one of more residues of an epitope comprising one or more residues of 79EVQTCSERRPIR90, 48NVTLTCRLLGPV60, 153HHHSEHRVHGAM164, 52LTCRLLGPV60, 56LLGPVDKGHDVTFYK70, 113LAQRHGLESASDHHG127, 153HHHSEHRVHGAM164, 93TFQDLHLHHGGHQAA107, 146CLVVEIRHHHSEH158, 53TCRLLGPVDKG63, 123SDHHG127 and/or 153HHHSEHRVHGAM164.

The invention aims to provide agonistic antibodies or fragments thereof that contain an antigen-binding region that specifically binds human VISTA, wherein the agonistic antibodies or fragments interact with or bind to one or more residues in an epitope containing one or more residues from 79EVQTCSERRPIR90.

It is a particular object of the present invention to provide an agonistic antigen or antibody fragment thereof that binds specifically to human VISTA, wherein the agonistic antibodies or fragments promote or enhance at least one effect on immunity of human VISTA, e.g. Its suppressive effect on T cell immunity; activation of monoocytes; induction T-cell proliferation, induction or inhibition of cytokine production, increased survival of Monocytes; induction or suspension of cytokine, and induction or suppression ADCC in cells expressing VISTA.

The invention aims to provide an agonistic antigen-binding region or an antibody fragment thereof that binds specifically to human VISTA. This agonistic antigen-binding region or fragment comprises variable heavy or light sequences that have the same CDR polypeptides of any of the antihuman VISTA antibodies that are shown in FIG. 4A-4JJ with the proviso, that if the said fragment or antibody comprises an antagonist antihuman VISTA antibodies or antibody fragment, then the antibody fragment or antibody does not contain the same CDRs of VSTB112, VSTB116 or VSTB95.

The invention aims to provide an agonistic antigen-binding region or an antibody fragment that specifically binds human VISTA, wherein the agonistic antigen-binding region or antibody contains an antagonist antihuman VISTA antigen or fragment, and the antibody or the fragment does not contain the same CDRs of VSTB112, VSTB116 VSTB95 VSTB50 VSTB53 VSTB60.

The invention aims to provide an agonistic antigen-binding region or an antibody fragment thereof that specifically binds human VISTA, wherein said agonistic antigen-binding region or fragment comprises a heavy polypeptide and/or a light polypeptide with at least 90% sequence similarity to an anti-human VISTA selected from VSTB49 -VSTB116. FIG. The CDRs of the anti-human VISTA antibodies or fragments are shown in FIGS. 4A-4JJ. However, if the antibody or fragment is an antagonist, then it must not contain the same CDRs.

The invention aims to provide an agonistic antigen or antibody fragment comprising an antigen-binding region that specifically binds human VISTA, wherein said agonistic antigen or antibody contains an antigen-binding region that specifically binds human VISTA and wherein such agonistic antigen or antibody fragment includes a variable heavy polypeptide and/or a variable light polypeptide with at least 95% identity in sequence to that of an antihuman VISTA antibodies selected from any of VSTB49 VSTB116. The invention provides a agonistic antibody or an antibody fragment thereof comprising an antigen binding region that specifically binds to human VISTA, wherein the agonistic antibody or antibody comprises a variable heavy and/or variable light polypeptide having at least 95% sequence identity to those of an anti-human VISTA antibodies selected from any one of VSTB49-VSTB116.

The invention aims to provide an agonistic antigen-binding region or an antibody fragment thereof that binds specifically to human VISTA, wherein said agonistic antigen-binding region or fragment comprises a heavy polypeptide and/or a light polypeptide with at least 96-95% sequence identity to an anti-human VISTA selected from VSTB49 to VSTB116. FIG. 4A-4JJ with the proviso, that if the antibody or fragment is an antagonist antihuman VISTA antibodies or antibody fragments, then the antibody/fragment does not contain the same CDRs of VSTB112, VSTB116 or VSTB95.

The invention aims to provide an agonistic antigen-binding region or an antibody fragment thereof that binds specifically to human VISTA, the agonistic antigen-binding region or fragment comprising a variable heavy polypeptide and/or variable polypeptide which are identical to those of a selected anti-human VISTA antibodies from VSTB49 to VSTB116. FIG. 4A-4JJ shows the variable heavy polypeptide and the light polypeptide of said antigen-binding 4A-4JJ with the proviso, that if the antibody or fragment is an antagonist antihuman VISTA antibodies or antibody fragments, then the antibody/fragment does not contain the same CDRs of VSTB112, VSTB116 VSTB95 VSTB50 VSTB53 VSTB60.

The invention aims to provide antagonistic antibodies or fragments of antigen-binding antibodies that bind to human VISTA in accordance with any of the above and which block or antagonize at least one immune effect of human VISTA.

It is a particular object of the present invention to provide an agonistic antigen or an antibody fragment thereof that binds specifically to human VISTA in accordance with any of the above which agonizes, or promotes, at least one human VISTA effect on immunity.

The invention aims to provide a agonistic antigen or an antibody fragment that binds specifically to human VISTA, according to the above which contains a constant domain.

It is a particular object of this invention to provide agonistic antibodies or antibody fragments thereof that contain an antigen-binding region that specifically binds human VISTA, according to the above, which includes a constant domain of human IgGI selected from IgG2, IgG3, and IgG4, optionally modified by deletion, addition, or substitution mutations, or any combination.

Click here to view the patent on Google Patents.