The University of Birmingham

The General Hospital Corporation

University of Virginia Patent Foundation

Dna Twopointo Inc.

Revitope Limited

Mark Cobbold

David Millar

Donald F Hunt

Jeffrey Shabanowitz

Marcela V Maus

Victor H Engelhard

Kara L Cummings

Rebecca C Obeng

Stacy Alyse Malaker

Jeremy S Minshull

Maggie Lee

Angela Lee Zarling

Angela L Ambakhutwala

Irene Scarfo

Sarah Amy Penny

Matthew Frigault

Feng Shi

Jennifer G Abelin

Yifang Shui

The invention provides modified an isolated T lymphocytes having reduced or eliminated expression of the T Cell Receptor, due to reduced or eliminated expression of a CD3ζ, T Cell Receptor Alpha Chain, or T Cell Receptor Beta Chain gene relative to a T lymphocyte without modification, where the isolated T lymphocyte expresses a protein comprising US6, UL40 viral protein and signal peptide, and UL18.

Modified T cells and methods of their use

Modified immune cells are provided, the modified immune cells expressing a heterologous polynucleotide comprising a nucleotide sequence encoding a function (e.g., at least one of persistence, proliferation, or cytotoxicity) booster, e.g., an apoptosis inhibitor. In one aspect, the modified T cells further comprise a chimeric antigen receptor. Methods, kits, and components for making and using the modified immune cells are also provided.

Modification of CAR-T cells

A set of target peptides are presented by HLA A*0101, A*0201, A*0301, B*4402, B*2705, B*1402, and B*0702 on the surface of disease cells. They are envisioned to among other things (a) stimulate an immune response to the proliferative disease, e.g., cancer, (b) to function as immunotherapeutics in adoptive T cell therapy or as a vaccine, (c) facilitate antibody recognition of tumor boundaries in surgical pathology samples, (d) act as biomarkers for early detection and/or diagnosis of the disease, and (e) act as targets in the generation antibody-like molecules which recognize the target-peptide/MHC complex.

Target peptides for immunotherapy and diagnostics

Described herein are methods for producing and utilizing an alternative signal 1 domain to construct an optimally signaling CAR. Alternative signal 1 domains of the present technology are based on alternatives to CD3&#x3b6;, including mutated ITAMs from CD3&#x3b6; (which contains 3 IT AM motifs), truncations of CD3&#x3b6;, and alternative splice variants known as CD3s, CD3 theta, and artificial constructs engineered to express fusions between CD3s or CD30 and CD3&#x3b6;. CAR polypeptides comprising alternative signal 1 domains are utilized to engineer CAR T cells. Further, this technology related to methods of treating cancer by administering to a subject in need thereof CAR T cells comprising alternative signal 1 domains.

Chimeric antigen receptors based on alternative signal 1 domains

The invention provides an agent for preventing or treating a condition characterised by the presence of unwanted cells, the agent comprising: (i) a targeting moiety that is capable of targeting to the unwanted cells; and (ii) a T cell antigen, wherein the T cell antigen can be released from the targeting moiety by selective cleavage of a cleavage site in the agent in the vicinity of the unwanted cells.

Re-directed immunotherapy

A set of target peptides are presented by HLA A*0201, B*0301, B*0702 and B*2705 on the surface of disease cells. They are envisioned to, among other things, stimulate an immune response to the proliferative disease, e.g., colorectal cancer, to function as immunotherapeutics in adoptive T cell therapy or as a vaccine, facilitate antibody recognition of tumor boundaries in surgical pathology samples, act as biomarkers for early detection and/or diagnosis of the disease, and/or act as targets in the generation antibody-like molecules which recognize the target-peptide/MHC complex.

Target peptides for colorectal cancer therapy and diagnostics

A variety of targeting moiety peptide epitope complexes (TPECs) are described in different embodiments. In each of the embodiments, however, a targeting moiety may be used to deliver the TPEC to an area of unwanted cells, allowing for a therapeutic effect to be delivered locally. The TPEC also contains a plurality of T-cell epitopes. The TPEC further comprises cleavage sites that release the T-cell epitopes from the targeting agent, and in some embodiments from each other, when they are in the microenvironment of the unwanted cells. Although the arrangement and number of T-cell epitopes varies in different embodiments described herein, once cleaved from the targeting agent (and any neighboring T-cell epitopes), the T-cell epitopes function by stimulating an immune response against the unwanted cells.

Targeting moiety peptide epitope complexes having a plurality of T-cell epitopes

The invention provides molecule comprising:

Immunotherapeutic molecules and uses

A targeted T-cell engaging agent for treating a condition characterized by the presence of unwanted cells includes (a) a targeting moiety that is capable of targeting the unwanted cells; (b) a first T-cell engaging domain capable of T-cell engaging activity when binding a second T-cell engaging domain, wherein the second T-cell engaging domain is not part of the agent; (c) at least one inert binding partner capable of binding to the first T-cell engaging domain such that the first T-cell engaging domain does not bind to the second T-cell engaging domain unless the inert binding partner is removed; and (d) at least one cleavage site separating the first T-cell engaging domain and the inert binding partner, wherein the cleavage site is: (i) cleaved by an enzyme expressed by the unwanted cells; (ii) cleaved through a pH-sensitive cleavage reaction inside the unwanted cell; (iii) cleaved by a complement-dependent cleavage reaction; or (iv) cleaved by a protease that is colocalized to the unwanted cell by a targeting moiety that is the same or different from the targeting moiety in the agent.

Functional antibody fragment complementation for a two-components system for redirected killing of unwanted cells

The invention provides molecule comprising: (i) a targeting moiety capable of directly or indirectly targeting to unwanted cells, and (ii) a further moiety that has a masked immune cell binding region so as to prevent binding of the further moiety to an immune cell, wherein the masked immune cell binding region is capable of being selectively unmasked when the molecule is in the vicinity of the unwanted cells so as to allow binding of the further moiety to an immune cell.

The invention provides an agent for preventing or treating a condition characterized by the presence of unwanted cells, the agent comprising: (i) a targeting moiety that is capable of targeting to the unwanted cells; and (ii) a T cell antigen, wherein the T cell antigen can be released from the targeting moiety by selective cleavage of a cleavage site in the agent in the vicinity of the unwanted cells.

Growing community of inventors

Winchester, MA, United States of America

Mark Cobbold