45 results about "ROR1" patented technology

The invention discloses an ROR1 specific chimeric antigen receptor and an application thereof. The ROR1 specific chimeric antigen receptor is a protein formed through serially connecting scFv of anti-human ROR1, the hinge region and the transmembrane region of CD8alpha, the transmembrane region and the intracellular region of CD28 and the intracellular region of CD3zeta from the amino end to the carboxyl end. T cells modified with the chimeric antigen receptor have a specific killing effect on tumor cells, and are expected to be in widely used in treatment of all kinds of solid tumor and blood tumors.

The present invention relates to Tri-Specific Binding Molecules, which are multichain polypeptide molecules that possess three Binding Domains and are thus capable of mediating coordinated binding to three epitopes. The Binding Domains may be selected such that the Tri-Specific Binding Molecules are capable of binding to any three different epitopes. Such epitopes may be epitopes of the same antigen or epitopes of two or three different antigens. In a preferred embodiment, one of such epitopes will be capable of binding to CD3, the second of such epitopes will be capable of binding to CD8, and the third of such epitopes will be capable of binding to an epitope of a Disease-Associated Antigen. The invention also provides a novel ROR1-binding antibody, as well as derivatives thereof and uses for such compositions.

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a ROR1 monoclonal antibody, conferring specific immunity against ROR1 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia, and for solid tumors such as breast, colon, lung, and kidney tumors

The present invention is directed to optimized ROR1-binding molecules having enhanced affinity and superior ability to mediate redirected cytotoxicity of tumor cells relative to prior ROR1-binding molecules. More specifically, the invention relates to optimized ROR1-binding molecules that comprise Variable Light Chain and / or Variable Heavy Chain (VH) Domains that have been optimized for binding to an epitope present on the human ROR1 polypeptide so as to exhibit enhanced binding affinity for human ROR1 and / or a reduced immunogenicity upon administration to recipient subjects. The invention particularly pertains to bispecific, trispecific or multispecific ROR1-binding molecules, including bispecific diabodies, BiTEs, bispecific antibodies, trivalent binding molecules, etc. that comprise: (i) such optimized ROR1-binding Variable Domains and (ii) a domain capable of binding to an epitope of a molecule present on the surface of an effector cell. The invention is also directed to pharmaceutical compositions that contain any of such ROR1-binding molecules, and to methods involving the use of any of such ROR1-binding molecules in the treatment of cancer and other diseases and conditions.

The invention discloses an anti-ROR1 safe chimeric antigen receptor modified immune cell and application thereof. An immune cell is modified by an anti-ROR1 safe chimeric receptor to obtain the anti-ROR1 safe chimeric antigen receptor modified immune cell. The anti-ROR1 safe chimeric antigen receptor comprises a CD8 leader, an ROR1 binding region, a CD8 hinge region, a transmembrane-stimulus domain, a CD3zeta-stimulus signal transduction region and a safety switch element; the immune cell and application thereof, provided by the invention have the advantages that untoward effects caused by cell transduction can be effectively avoided and clinical efficacy and safety of a CAR technology are greatly improved.

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a ROR1 monoclonal antibody, conferring specific immunity against ROR1 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia, and for solid tumors such as breast, colon, lung, and kidney tumors

The invention relates to a targeted rabbit-source ROR1 chimeric antigen receptor and application thereof, and particularly provides polynucleotide sequences. The polynucleotide sequences are selectedfrom (1) polynucleotide sequences containing a coding sequence of an anti-ROR1 single-chain antibody, a coding sequence of a human CD8alpha hinge region, a coding sequence of a human CD8 transmembraneregion, a coding sequence of a human 41BB intracellular region and a coding sequence of a human CD3zeta intracellular region, wherein the coding sequences are sequentially connected; (2) complementary sequences of the polynucleotide sequences (1). The invention further provides relevant fusion protein, a carrier containing the coding sequences and application of the fusion protein, the coding sequences and the carrier. Prepared ROR1(R12)-BBz CAR-T cells have a strong killing function on specific tumor cells, and IFNgamma secretion is high.

The invention provides a preparation method of PD1-knockout chimeric antigen receptor T cell targeting ROR1. The method comprises: linking an encoding gene of the chimeric antigen receptor CAR-ROR1 toa vector, and constructing the recombinant lentivirus, performing transfection on CD3 positive T lymphocytes, and performing knockout of the PD1 gene of the transfected T cells to obtain the PD1-knockout chimeric antigen receptor T cell targeting ROR1. The knockout of the PD1 gene by the chimeric antigen receptor T cell is in favor of amplification of T cells in the patient, and avoids the escapeof immunosurveillance of the tumor cells, the T cell has the performance of killing tumor cells with high efficiency and specificity, which maintains the viability and lethality of the cells for a long time and does not cause damage to normal cells.

The present invention provides a single-chain antibody targeting ROR1, the single-chain antibody targeting ROR1 comprises an amino acid sequence shown in SEQ ID NO: 1. The present invention also provides a chimeric antigen receptor T cell comprising the single-chain antibody targeting ROR1, wherein the chimeric antigen receptor targeting ROR1 can specifically target ROR1, the cellular immunity effect of T cells can be activated, the ROR1 positive tumor cells can be efficiently and specifically killed, the chimeric antigen receptor has lasting cell vitality and lethality, and damage is hardly generated on the normal cells. The invention also provides a preparation method and an application of the chimeric antigen receptor T cell targeting ROR1.

The embodiments of the present invention provide a bispecific chimeric antigen receptor, consisting of a signal peptide, two specific antigen-binding fragments, an extracellular spacer region, a transmembrane region, an intracellular co-stimulatory signaling domain, the first antigen that is recognized and bound by the specific antigen-binding fragments is a member selected from the group consisting of CD19, CD20, CD22, CD33, CD269, CD138, CD79a, CD79b, CD23, ROR1, CD30, B cell surface antibody light chain, CD44, CD123, Lewis Y, CD7 and CD46; the second antigen that is recognized and bound by the specific antigen-binding fragments is CD38, the two specific antigen-binding fragments is linked by a linker peptide, the bispecific chimeric antigen receptor can recognize respectively two kinds of tumor-associated antigens by constructing low affinity chimeric antigen receptors and high affinity chimeric antigen receptors and have very strong specificity. In addition, the embodiments of the present invention also provide a use of the bispecific chimeric antigen receptor in the treatment of tumors.

The invention discloses a chimeric anti-ROR1 antibody Fab molecule as well as a preparation method and application thereof. The chimeric anti-ROR1 antibody Fab molecule includes a recombinant light chain L and a recombinant heavy chain Fd which are linked by disulfide bonds between the chains, the amino acid sequence of the recombinant light chain L is shown as SEQ ID NO.1, and the amino acid sequence of the recombinant heavy chain Fd is shown as SEQ ID NO.2. The chimeric anti-ROR1 antibody Fab molecule provided by the invention greatly reduces mouse-derived components of an anti-ROR1 antibodyand still preserves the characteristics of a human-mouse cross reaction, thereby facilitating further experiments in vivo; the mimic antigen characteristics of a mouse-derived antibody are retained,and the chimeric anti-ROR1 antibody Fab molecule can potentially be used for targeting therapy of ROR1 high-expression tumors; a prokaryotic expression vector is easy to construct, can be expressed inlarge quantities, and is produced rapidly and convenient for purification; and the preparation of a chimeric whole-molecule antibody or humanization modification of the antibody are facilitated, andthe mouse-derived components of the anti-ROR1 antibody are further reduced for developing targeting therapy research of the ROR1 high-expression tumors.

The invention provides improved compositions for adoptive cell therapies for cancers that express ROR1.

The invention relates to chimeric antigen receptors (CAR) with a humanized targeting domain specific to the antigen ROR1. The invention encompasses the polynucleotides, vectors encoding said CARs and the isolated cells expressing them at their surface, in particularly for their use in immunotherapy.

Chimeric antigen receptors containing ROR1 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions,relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.

The invention provides an application of hsa_circ_0006470 as a target in preparation of a miR-27b-3p regulator, and other applications of the hsa_circ_0006470. The inventor finds that miR-27b-3p and the hsa_circ_0006470 have interaction through a dual luciferase report experiment, and finds that the expression of the miR-27b-3p can be improved by silencing the hsa_circ_0006470 through an RNAi (Ribonucleic Acid Interference) experiment, so that a downstream pathway of the miR-27b-3p, such as ROR1 (Restricted Osteogen Receptor 1), can be further influenced to further inhibit the proliferation and migration capabilities of gastric cancer cells, and in addition, the expression of PIK3CA can be inhibited to promote an autophagy effect; and the PIK3CA is overexpressed in the cancer cells with the silent hsa_circ_0006470, so that the phenotype caused by the silent hsa_circ_0006470 can be relieved. The results show that the hsa_circ_0006470 has a close relationship with the miR-27b-3p, the PIK3CA, the proliferation and migration of the gastric cancer cells, the autophagy effect of the cells and the like, therefore, the application of the hsa_circ_0006470 serving as the target in preparation of the miR-27b-3p regulator, a PIK3CA regulator, autophagy and autophagy-related disease drugs and cancer treatment drugs and the application of the hsa_circ_0006470 serving as a molecular marker in preparation of cancer diagnostic reagents have huge potential values.

A compound of formula (I′) or (I″) or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of mammalian kinase enzyme activity, including ROR1 tyrosine kinase activity and may be used in the treatment of disorders associated with such activity.

The present invention relates to a multi-specific product comprising a first entity comprising an antigen-binding domain that binds to the same ROR1 epitope as and / or competes for ROR1 binding with an antibody comprising a heavy chain variable region sequence shown in SEQ ID NO. 2 and a light chain variable region sequence shown in SEQ ID NO. 3; and a second entity comprising an antigen-binding domain that binds to a different target or ROR1 epitope than, and / or does not compete for binding with the antibody comprising a heavy chain variable region sequence shown in SEQ ID NO. 2 and a light chain variable region sequence shown in SEQ ID NO. 3.

The invention provides a method for constructing a targeting ROR1 CAR-T cell by using shRNA (short hairpin ribonucleic acid) to silence a human Tim-3 gene and application of the targeting ROR1 CAR-T cell. The HKP55 CAR-T cell prepared by the method can be applied to cancer treatment. According to the invention, three different targeting Tim-3 genes with small hairpin RNA (shRNA) sequence specificity are designed, and the shRNA-3 sequence with the best silencing effect is obtained through screening. Therefore, the shRNA-3 sequence and the CAR sequence of the targeted ROR1 are co-transfected into the T cell, and the ROR1 CAR-T (HKP55 CAR-T) cell with the silent Tim-3 gene is prepared. The Tim-3 expression level of HKP55 CAR-T cells is greatly reduced, and compared with ROR1 CAR-T (HKP69 CAR-T) cells, the in-vitro killing of the ROR1 CAR-T cells on target cells with high expression of Galectin-9 and cell proliferation dependent on the target cells are remarkably enhanced through silencing of the Tim-3 gene. Therefore, the HKP55 CAR-T cell can overcome a complex immunosuppressive tumor microenvironment, continuously proliferate and exert an anti-tumor effect function.

The present invention relates to a new generation of chimeric antigen receptors (CAR) referred to as multi-chain CARs, which are made specific to the antigen ROR1. Such CARs aim to redirect immune cell specificity and reactivity toward malignant cells expressing the tumor antigen ROR1. The alpha, beta and gamma polypeptides composing these CARs are designed to assemble in juxtamembrane position, which forms flexible architecture closer to natural receptors, that confers optimal signal transduction. The invention encompasses the polynucleotides, vectors encoding said multi-chain CAR and the isolated cells expressing them at their surface, in particularly for their use in immunotherapy. The invention opens the way to efficient adoptive immunotherapy strategies for treating cancer, especially chronic lymphocytic leukemia or solid tumors.

The invention discloses an anti-ROR1 safe chimeric antigen receptor modified immune cell and application thereof. An immune cell is modified by an anti-ROR1 safe chimeric receptor to obtain the anti-ROR1 safe chimeric antigen receptor modified immune cell. The anti-ROR1 safe chimeric antigen receptor comprises a CD8 leader, an ROR1 binding region, a CD8 hinge region, a transmembrane-stimulus domain, a CD3zeta-stimulus signal transduction region and a safety switch element; the immune cell and application thereof, provided by the invention have the advantages that untoward effects caused by cell transduction can be effectively avoided and clinical efficacy and safety of a CAR technology are greatly improved.

The invention provides a bispecific chimeric antigen receptor (CAR) targeting ROR1 and CD7 and application thereof, the bispecific chimeric antigen receptor (CAR) has the following structure: ROR1 scFv-CD7 scFv-H-TM-C-CD3 zeta, in which "-" is a connecting peptide or a peptide bond; H is a hinge area; TM is a transmembrane domain; C is a costimulatory signal molecule; and CD3zeta is an intracellular signal transduction sequence. The chimeric antigen receptor can inhibit tumor growth in vivo and in vitro, prolong the life cycle, promote cytokine secretion and play a synergistic anti-tumor role.

A compound of formula (I′) or (I″)or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of mammalian kinase enzyme activity, including ROR1 tyrosine kinase activity and may be used in the treatment of disorders associated with such activity.