Antibodies specific to delta 1 chain of T cell receptor
Inventors
Koide, Shohei • Miller, George • Koide, Akiko • Panchenko, Tatyana • Hattori, Takamitsu • Filipovic, Aleksandra • Elenko, Eric • Bolen, Joseph
Assignees
New York University NYU • Puretech LYT Inc • Puretech Health LLC
Publication Number
US-12084500-B2
Publication Date
2024-09-10
Expiration Date
2040-01-23
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Abstract
Disclosed herein are antibodies specific to a delta-1 chain of a γδ T cell receptor and methods of using such for modulating γδ T cell bioactivity. Such anti-Delta 1 antibodies may also be used to treat diseases associated with γδ T cell activation, such as solid tumors, or for detecting presence of γδ1 T cells.
Core Innovation
The invention provides isolated antibodies that specifically bind to the delta-1 chain of a γδ T cell receptor. These antibodies can modulate γδ T cell bioactivity by binding this target, leading to suppression of γδ T cells, and thereby rescuing immune suppression otherwise mediated by these cells. The specificity of the antibodies is detailed by their defined complementarity determining regions (CDRs), with explicit sequences provided for both heavy and light chains. The antibodies may be full-length IgG molecules or antigen-binding fragments and can include human, humanized, or antibody mimetic forms.
The problem addressed is the need for new cancer therapies, as many cancers are refractory to current immune checkpoint blockade treatments targeting pathways such as CTLA-4 and PD-1, which have significant non-response rates. γδ T cells, particularly those expressing the delta-1 chain, have been implicated in promoting tumor progression and creating an immunosuppressive tumor microenvironment. By developing antibodies that specifically target the delta-1 chain, the invention offers a new therapeutic approach to modulate γδ T cell activity, thus potentially improving cancer treatment outcomes.
The antibodies disclosed not only suppress the immunosuppressive activity of γδ T cells but can also deplete these cells via mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). They may be used in combination with existing therapies, including checkpoint inhibitors, chemotherapeutic agents, and other anti-cancer agents. Additionally, these antibodies can be used to detect the presence of γδ1 T cells in biological samples to aid in the diagnosis and selection of appropriate treatment strategies.
Claims Coverage
The patent includes two independent claims covering two main inventive features related to isolated antibodies that specifically bind a delta-1 chain of a T cell receptor and their defined molecular characteristics.
Antibody binding a delta-1 chain of a T cell receptor defined by specific CDR sequences
An isolated antibody that binds a delta-1 chain of a T cell receptor, wherein the antibody comprises: - A heavy chain complementarity determining region 1 (VH-CDR1) set forth as SEQ ID NO: 68, - A heavy chain complementarity determining region 2 (VH-CDR2) set forth as SEQ ID NO: 53, - A heavy chain complementarity determining region 3 (VH-CDR3) set forth as SEQ ID NO: 54, - A light chain complementarity determining region 1 (VL-CDR1) set forth as SEQ ID NO: 55, - A light chain complementarity determining region 2 (VL-CDR2) set forth as SEQ ID NO: 56, - A light chain complementarity determining region 3 (VL-CDR3) set forth as SEQ ID NO: 57. This antibody covers full-length antibodies as well as antigen-binding fragments, single-chain antibodies, human or humanized antibodies, and various IgG subclasses, with allowed mutations, specified heavy and light chain constant regions.
Antibody defined by full heavy chain and light chain variable regions
An isolated antibody that comprises: - A heavy chain variable region (VH) set forth as SEQ ID NO: 24, - A light chain variable region (VL) set forth as SEQ ID NO: 9. This includes all antibody forms (full-length or fragment), human or humanized variants, specified IgG subclasses (IgG1 or IgG4), potential constant region sequences, and particular full sequences such as SEQ ID NO: 79 for the heavy chain and SEQ ID NO: 78 for the light chain.
Pharmaceutical composition comprising the antibody
A pharmaceutical composition comprising the above-described antibody and a pharmaceutically acceptable carrier.
Treatment method for inhibition of γδ T cell activation
A method of inhibiting γδ T cell activation in a subject by administering an effective amount of a pharmaceutical composition comprising the described isolated antibody, including application to human patients with solid cancers and including possible co-administration with checkpoint inhibitors, co-stimulatory receptor activators, chemotherapeutic or anti-hypertensive agents.
The claims cover isolated antibodies defined by specific CDR or variable region sequences that bind the delta-1 chain of T cell receptors, as well as their compositions and methods of use for γδ T cell inhibition, especially in cancer therapy.
Stated Advantages
The antibodies exhibit high binding affinity to multiple human delta-1 TCRs, regardless of CDR or CDR3 sequence.
The antibodies show cross-reactivity between human and non-human primate delta-1 TCRs, with similar binding affinity.
They bind delta-1 TCRs containing various gamma chains, providing broad target coverage.
The antibodies are highly specific for the delta-1 chain with little or no binding to other targets.
They inhibit γδ T cell-mediated suppression of T cell activation and can promote inflammatory T cell activation.
The antibodies can activate cytotoxic mechanisms including ADCC and ADCP for depletion of γδ T cells.
They can be used alone or in combination with existing anti-cancer therapies, potentially enhancing the efficacy of checkpoint inhibitors and chemotherapeutic agents.
The antibodies possess favorable thermostability and can be stored and handled under standard conditions without aggregation.
Documented Applications
Therapeutic treatment of solid tumors including pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, breast cancer, lung cancer, glioblastoma, upper and lower gastrointestinal malignancies, squamous cell head and neck cancer, genitourinary cancer, ovarian cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, neuroendocrine cancer, adrenocortical cancer, and sarcomas by inhibiting or modulating γδ T cell activity.
Use in combination therapy with immune checkpoint inhibitors (such as anti-PD-1, anti-PD-L1, anti-CTLA-4), chemotherapeutic agents, co-stimulatory receptor agonists, and anti-hypertensive agents for cancer treatment.
Detection of γδ1 T cells and measurement of Delta1 levels in biological samples (such as blood, plasma, serum, tumor biopsy, or PBMCs) using immunoassays, flow cytometry, or immunohistochemistry.
Identifying or selecting cancer patients likely to respond to anti-Delta1 antibody targeting therapy based on elevated Delta1 levels.
Elimination or depletion of immunosuppressive γδ T cells from the tumor microenvironment or circulation.
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