Chimeric antigen receptor (CAR) that binds specifically to CD70, genetically modified immune cell, pharmaceutical composition, and method of manipulating an immune cell.

Description

Chimeric antigen receptor (CAR) that binds specifically to CD70, genetically modified immune cell, pharmaceutical composition, and method of manipulating an immune cell. Separated from BR112020015662-0, filed on 01 / 31 / 2019. CROSS-REFERENCE TO RELATED ORDERS

[0001] This application claims priority over the Patent Application US Provisional Patent Application No. 62 / 775,246, filed December 4, 2018, US Provisional Patent Application No. 62 / 641,6869, filed March 12, 2018, US Provisional Patent Application No. 62 / 641,873, filed March 12, 2018, US Provisional Patent Application No. 62 / 625,009, filed February 1, 2018, and US Provisional Patent Application No. 62 / 625,019, filed February 1, 2018, which are incorporated herein by reference in their entirety. REFERENCE TO THE SEQUENCE LISTING

[0002] This application is filed electronically via EFS-Web and includes a sequence listing submitted electronically in .txt format. The .txt file contains a sequence listing titled ALGN_014_03WO_SeqList_ST25.txt created on January 24, 2019, and with a size of ~725 kilobytes. The sequence listing contained in this .txt file is an integral part of the descriptive report and is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0003] The description refers to chimeric antigen receptors (CARs). CARs are capable of redirecting immune cell specificity and reactivity to a selected target that exploits the properties of the ligand-binding domain. In particular, the description refers to CARs that specifically bind to Cluster of Differentiation 70 (CD70-specific CARs). The description also refers Petition 870260028237, dated 03 / 25 / 2026, p. 822 / 1082 2 / 230 to polynucleotides encoding CD70-specific CARs and isolated cells expressing CD70-specific CARs on their surface. The description also refers to methods for manipulating immune cells that express CD70-specific CARs on their surface. The description is particularly useful for the treatment of cancer, such as lymphoma, leukemia, glioma, or Renal Cell Carcinoma (RCC). The description also refers to immune cells comprising CD70-specific CARs (CD70-specific CAR-T cells), compositions comprising CD70-specific CAR-T cells, and methods for using CD70-specific CAR-T cells to treat conditions associated with malignant cells expressing CD70 (e.g., cancer). FUNDAMENTALS

[0004] Adoptive transfer of genetically modified immune cells to recognize antigens associated with malignancies has shown promise as a novel approach to treating cancer (see, for example, Brenner et al., Current Opinion in Immunology, 22(2): 251-257 (2010); Rosenberg et al., Nature Reviews Cancer, 8(4): 299-308 (2008)). T cells can be genetically modified to express chimeric antigen receptors (CARs), fusion proteins composed of an antigen recognition fraction and a T cell activation domain (see, for example, Eshhar et al., Proc. Natl. Acad. Sci. USA, 90(2): 720-724 (1993) and Sadelain et al., Curr. Opin. Immunol, 21(2): 215-223 (2009)).

[0005] The Cluster of Differentiation 70 (CD70, CD27LG or TNFSF7 is a member of the tumor necrosis factor (TNF) superfamily and the ligand for CD27, a TNF superfamily receptor. The transient interaction between CD27 and CD70 provides complementary T cell co-stimulation to that provided by CD28. CD70 is expressed in hematologic cancers such as non-Hodgkin lymphoma and Hodgkin's disease. Petition 870260028237, dated 03 / 25 / 2026, page 823 / 1082 3 / 230 gkin, as well as in solid tumors such as Glioblastoma and Renal Cell Carcinoma; where its expression in ccRCC is almost uniform (see, for example, Grewal I., et al., Expert Opinion on Therapeutic Targets, 12(3): 341-351 (2008)). Adoptive transfer of genetically modified T cells to recognize antigens associated with malignancies has shown promise as a new approach to treat cancer (see, for example, Brenner et al., Current Opinion in Immunology, 22(2): 251-257 (2010); Rosenberg et al., Nature Reviews Cancer, 8(4): 299-308 (2008)). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are fusion proteins composed of an antigen recognition fraction and a T cell activation domain (see, for example, Eshhar et al., Proc. Natl. Acad. Sci. USA, 90(2): 720-724 (1993), and Sadelain et al., Current Opinion in Immunology, 21(2): 215-223 (2009)).CD70 expression in normal tissues is limited to activated T cells, B cells, NK cells, and dendritic cells. However, CD70 expression in activated T cells may pose a concern for CAR T cell production due to potential T cell differentiation targeting, exhaustion, and fratricide during the production process.

[0006] Renal cell carcinoma (RCC) is a cancer that originates in the renal cortex and accounts for approximately 90% of kidney cancers. Based on histology, RCC can be classified into several subtypes, of which clear cell renal carcinoma (ccRCC) is the most common and leads to the majority of deaths. Every year, more than 320,000 cases of RCC are reported worldwide, leading to approximately 140,000 deaths. The incidence of RCC has gradually increased over the past 10 years and accounts for 2-3% of all adult malignancies. Patients with localized tumors in the early stages may opt for surgical resection; however, localized disease Petition 870260028237, dated 03 / 25 / 2026, pp. 824 / 1082 4 / 230 zada can undergo early hematogenous dissemination leading to metastasis. Sites of initial metastases include lungs, lymph nodes, liver, bones, and brain; less commonly, adrenal glands and contralateral kidney. Patients with advanced disease face high morbidity rates with a median 5-year survival rate of 53% for stage III disease and only 8% for metastatic disease. Current first-line treatment options for advanced disease include small molecule Tyrosine Kinase Inhibitors (TKIs) such as sunitinib and pazopanib that target the Vascular Endothelial Growth Factor (VEGF) receptor, monoclonal antibodies that target VEGF such as bevacizumab, mammalian Rapamycin inhibitor (mTOR) targeting, as well as high-dose IL-2.Although these VEGF-targeted therapies have a higher overall survival rate, long-term drug resistance leads to disease recurrence, and treatment for advanced disease remains an unmet need (see, for example, Zarrabi, K. et al., Journal of Hematology and Oncology, 10:38 (2017)).

[0007] In this sense, there is a need for alternative cancer treatments and, in particular, malignancies involving aberrant CD70 expression. New immunotherapies, such as CAR T-cell therapy, have the potential to significantly improve outcomes for cancer patients in whom CD70 is expressed, for example, in mRCC. Therefore, treatment for a cancer (such as, for example, mRCC) using CD70-specific CARs and CD70-specific CART cells would be a promising therapeutic agent. Methods and compositions that address this need are provided in this document. SUMMARY

[0008] chimeric antigen receptors (CARs) that bind to Petition 870260028237, dated 03 / 25 / 2026, page 825 / 1082 5 / 230 CD70s are provided in this document, as well as methods of manufacture and methods of use thereof. Also provided in this document are immune cells, for example, T cells comprising such CARs for CD70. It is demonstrated that certain CD70-specific CARs are effective when expressed on T cells to activate T cells upon contact with CD70. Advantageously, the CD70-specific CARs provided in this document bind to human CD70. Also advantageously, the CD70-specific CAR-T cells provided in this document exhibit cytotoxic activity upon contact with cells expressing CD70. Also provided in this document are antibodies that bind to CD70, as well as methods of manufacture and methods of use thereof. The CD70-specific antibodies provided in this document bind to human CD70.

[0009] In one aspect, the description provides a chimeric antigen receptor (CAR) specific for Cluster of Differentiation 70 (CD70) comprising an extracellular ligand-binding domain, a first transmembrane domain, and an intracellular signaling domain, wherein the extracellular domain comprises a single-chain Fv fragment (scFv) that binds to the extracellular domain of CD70.

[0010] In some embodiments, the description provides a specific CAR for CD70 wherein the extracellular domain of a CAR provided in this document comprises an scFv comprising a variable heavy chain (VH) region comprising three CDRs of the VH region comprising the sequence shown in SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381; and a variable light chain (VL) region comprising three CDRs of the VL region. Petition 870260028237, dated 03 / 25 / 2026, page 826 / 1082 6 / 230 shown in SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380.In some embodiments, the VH region comprises the sequence shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, or 381, or a variant thereof with one or more conservative amino acid substitutions at residues that are not within a CDR. and / or the VL region comprises the amino acid sequence shown in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380 or a variant thereof with one or more amino acid substitutions in amino acids that are not within a CDR.

[0011] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 49, 50 or 51; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 52 or 53; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 54; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 193; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 194; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 195.

[0012] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 2 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 1.

[0013] In some modalities, the VH region comprises a Petition 870260028237, dated 03 / 25 / 2026, page 827 / 1082 7 / 230 VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 55, 56 or 57; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 58 or 59; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 60; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 196; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 197; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 198.

[0014] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 4 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 3.

[0015] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 61, 62 or 63; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 64 or 65; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 66; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 199; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 200; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 201.

[0016] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 6 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 5.

[0017] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 67, 68 or 69; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 70 or 71; and a VH CDR3 comprising the amino acid sequence indicated in SEQ Petition 870260028237, dated 03 / 25 / 2026, page 828 / 1082 8 / 230 ID NO: 72; and a VL region comprises a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 202; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 203; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 204.

[0018] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 8 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 7.

[0019] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 73, 74 or 75; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 76 or 77; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 78; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 205; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 206; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 207.

[0020] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 10 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 9

[0021] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 79, 80, or 81; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 82 or 83; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 84; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 208; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 209; and a VL CDR3 comprising the sequence of Petition 870260028237, dated 03 / 25 / 2026, page 829 / 1082 9 / 230 amino acids indicated in SEQ ID NO: 210.

[0022] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 12 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 11.

[0023] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 85, 86 or 87; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 88 or 89; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 90; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 211; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 212; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 213. In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 14 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 13.

[0024] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 91, 92 or 93; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 94 or 95; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 96; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 214; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 215; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 216.

[0025] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 16 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 15. Petition 870260028237, dated 03 / 25 / 2026, pp. 830 / 1082 10 / 230

[0026] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 97, 98 or 99; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 100 or 101; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 102; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 217; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 218; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 219.

[0027] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 18 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 17.

[0028] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 103, 104 or 105; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 106 or 107; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 108; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 220; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 221; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 222.

[0029] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 20 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 19.

[0030] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 109, 110 or 111; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 112 or 113; and a Petition 870260028237, dated 03 / 25 / 2026, pp. 831 / 1082 11 / 230 VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 114; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 223; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 224; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 225.

[0031] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 22 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 21.

[0032] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 115, 116 or 117; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 118 or 119; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 120; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 226; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 227; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 228.

[0033] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 24 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 23.

[0034] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 121, 122, or 123; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 124 or 125; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 126; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 229; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 124 or 125; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 126. Petition 870260028237, dated 03 / 25 / 2026, page 832 / 1082 12 / 230 each in SEQ ID NO: 230; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 231.

[0035] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 26 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 25.

[0036] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 127, 128 or 129; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 130 or 131; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 132; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 232; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 233; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 234.

[0037] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 28 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 27.

[0038] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 133, 134 or 135; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 136 or 137; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 138; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 235; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 236; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 237.

[0039] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 30 and the VL region Petition 870260028237, dated 03 / 25 / 2026, page 833 / 1082 13 / 230 comprises the amino acid sequence indicated in SEQ ID NO: 29.

[0040] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 139, 140 or 141; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 142 or 143; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 144; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 238; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 239; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 240.

[0041] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 32 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 31.

[0042] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 145, 146 or 147; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 148 or 149; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 150; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 241; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 242; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 243.

[0043] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 34 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 33.

[0044] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 151, 152 or 153; a VH CDR2 comprising the sequence... Petition 870260028237, dated 03 / 25 / 2026, page 834 / 1082 14 / 230 amino acid sequence indicated in SEQ ID NO: 154 or 155; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 156; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 244; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 245; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 246.

[0045] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 36 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 35.

[0046] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 157, 158 or 159; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 160 or 161; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 162; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 247; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 248; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 249.

[0047] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 38 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 37.

[0048] In some embodiments, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 163, 164, or 165; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 166 or 167; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 168; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: Petition 870260028237, dated 03 / 25 / 2026, page 835 / 1082 15 / 230 250; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 251; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 252.

[0049] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 40 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 39.

[0050] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 169, 170 or 171; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 172 or 173; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 174; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 253; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 254; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 255.

[0051] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 42 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 41.

[0052] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 175, 176 or 177; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 178 or 179; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 180; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 256; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 257; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 258.

[0053] In some modalities, the VH region comprises the se Petition 870260028237, dated 03 / 25 / 2026, page 836 / 1082 16 / 230 amino acid sequence indicated in SEQ ID NO: 44 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 43.

[0054] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 181, 182 or 183; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 184 or 185; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 186; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 259; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 260; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 261.

[0055] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 46 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 45.

[0056] In some modalities, the VH region comprises a VH CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 187, 188 or 189; a VH CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 190 or 191; and a VH CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 192; and a VL region comprising a VL CDR1 comprising the amino acid sequence indicated in SEQ ID NO: 262; a VL CDR2 comprising the amino acid sequence indicated in SEQ ID NO: 263; and a VL CDR3 comprising the amino acid sequence indicated in SEQ ID NO: 264.

[0057] In some embodiments, the VH region comprises the amino acid sequence indicated in SEQ ID NO: 48 and the VL region comprises the amino acid sequence indicated in SEQ ID NO: 47.

[0058] In some modalities, each CDR is defined according to the Kabat definition, the Chothia definition, the combination of Petition 870260028237, dated 03 / 25 / 2026, page 837 / 1082 17 / 230 Kabat definition and Chothia definition, the AbM definition or the CDR contact definition.

[0059] In some embodiments, each CDR is defined according to the Kabat definition, the Chothia definition, the extended definition, the combination of the Kabat definition and the Chothia definition, the AbM definition or the contact definition and / or the conformational definition of the CDRs.

[0060] In some embodiments, the intracellular signaling domain comprises a CD3Z signaling domain. In some embodiments, the intracellular signaling domain comprises a 4-1BB domain. In some embodiments, the CAR further comprises a second intracellular signaling domain. In some embodiments, the second intracellular signaling domain comprises a 4-1BB domain. In some embodiments, the CAR comprises a first CD3Z intracellular signaling domain and a second 4-1BB intracellular signaling domain.

[0061] In some embodiments, the intracellular signaling domain comprises a CD3Z signaling domain. In some embodiments, the intracellular signaling domain comprises a 4-1BB domain. In some embodiments, the CAR further comprises two intracellular signaling domains. In some embodiments, the CAR further comprises 3, 4, 5, or 6 intracellular signaling domains. In some embodiments, the CAR comprises a first intracellular signaling domain and a second intracellular signaling domain, wherein the second intracellular signaling domain comprises a 4-1BB domain. In some embodiments, the CAR comprises a CD3Z intracellular signaling domain and a second 4-1BB intracellular signaling domain.

[0062] In some forms, the CAR may also include a stalk domain between the extracellular ligand-binding domain and the Petition 870260028237, dated 03 / 25 / 2026, page 838 / 1082 18 / 230 first transmembrane domain. In some embodiments, the stalk domain is selected from the group consisting of: a human CD8a hinge, an IgG1 hinge, and an FcYRIIIa hinge. In some embodiments, the stalk domain is a human CD8a hinge, a human IgG1 hinge, or a human FcYRIIIa hinge.

[0063] In some embodiments, the CAR may comprise an epitope of CD20. In some embodiments, the CD20 epitope comprises the amino acid sequence indicated in SEQ ID NO: 293 or SEQ ID NO: 294 or SEQ ID NO: 609.

[0064] In some embodiments, the CAR may comprise the amino acid sequence indicated in SEQ ID NO: 311 to 334 listed in Table 5. In some embodiments, the CAR may comprise the amino acid sequence indicated in SEQ ID NO: 319 or 327.

[0065] In some embodiments, the first transmembrane domain comprises a CD8α chain transmembrane domain.

[0066] In some embodiments, the CAR may comprise another extracellular ligand-binding domain that is not specific to CD70.

[0067] In some embodiments, the extracellular ligand-binding domains, the first transmembrane domain, and the intracellular signaling domains are in a single polypeptide.

[0068] In some embodiments, the CAR may further comprise a second transmembrane domain, wherein the first transmembrane domain and the extracellular ligand-binding domain(s) are in a first polypeptide, and wherein the second transmembrane domain and the intracellular signaling domain(s) are in a second polypeptide, wherein the first transmembrane domain comprises a transmembrane domain of the α chain of the high-affinity IgE receptor (FcεRI) and the second transmembrane domain Petition 870260028237, dated 03 / 25 / 2026, page 839 / 1082 19 / 230 brane comprises a transmembrane domain of the γ or β chain of FceRI.

[0069] In some embodiments, the CAR may further comprise a third polypeptide comprising a third transmembrane domain fused to an intracellular signaling domain of a co-stimulatory molecule, wherein the third transmembrane domain comprises a transmembrane domain of the γ or β chain of FcεRI.

[0070] In another aspect, the description provides an isolated polynucleotide comprising a nucleic acid sequence encoding the specific CAR for CD70 described in this document.

[0071] In another aspect, the description provides an expression vector comprising the polynucleotide encoding the specific CAR for CD70 described in this document.

[0072] In another aspect, the description provides a manipulated immune cell that expresses on its cell surface membrane a CD70-specific CAR described in this document. In some embodiments, the manipulated immune cell may comprise another CAR that is not CD70-specific. In some embodiments, the manipulated immune cell may comprise a polynucleotide encoding a suicide polypeptide. In some embodiments, the suicide polypeptide is RQR8.

[0073] In some modalities, the manipulated immune cell is derived from an inflammatory T lymphocyte, a cytotoxic T lymphocyte, a regulatory T lymphocyte, or a helper T lymphocyte.

[0074] In some embodiments, the manipulated immune cell may comprise a disruption of one or more endogenous genes, wherein the endogenous gene encodes TCRa, TCRe, CD52, glucocorticoid receptor (GR), deoxycytidine kinase (dCK), CD70, or an immune checkpoint protein such as programmed death protein-1 (PD-1). Petition 870260028237, dated 03 / 25 / 2026, pp. 840 / 1082 20 / 230

[0075] In some modalities, the manipulated immune cell is obtained from a healthy donor. In some modalities, the manipulated immune cell is obtained from a patient.

[0076] In another aspect, the description provides a engineered immune cell that expresses on its cell surface membrane a specific CAR for CD70 described in this document for use as a medicine. In some embodiments, the medicine is for use in the treatment of cancer. In some embodiments, the medicine is for the treatment of Renal Cell Carcinoma, glioblastoma, glioma, such as low-grade glioma, non-Hodgkin lymphoma (NHL), Hodgkin disease (HD), Waldenstrom's macroglobulinemia, acute myeloid leukemia, multiple myeloma, diffuse large cell lymphoma, follicular lymphoma, or non-small cell lung cancer.

[0077] In another aspect, the description provides a method for manipulating an immune cell comprising: providing an immune cell; and expressing on the cell surface at least one CD70-specific CAR, as described in this document. In some embodiments, the method comprises: providing an immune cell; introducing into the cell at least one polynucleotide encoding said CD70-specific CAR; and expressing said polynucleotide on the cell.

[0078] In some embodiments, the method comprises providing an immune cell; introducing into the cell at least one polynucleotide encoding the said CAR specific to CD70; and introducing at least one other CAR that is not specific to CD70.

[0079] In another aspect, the description provides a method for treating a subject suffering from a condition associated with malignant cells, the method comprising: providing an immune cell that expresses on its surface a specific CAR for CD70 as described. Petition 870260028237, dated 03 / 25 / 2026, pp. 841 / 1082 21 / 230 in this document; and administer the aforementioned immune cells to the aforementioned patient.

[0080] In another aspect, the description provides a pharmaceutical composition comprising an immune cell manipulated as described in this document.

[0081] In another aspect, the description provides a method for treating a condition associated with malignant cells expressing CD70 in a subject comprising administering to a subject in need an effective amount of a pharmaceutical composition comprising a manipulated immune cell, as described in this document. In some embodiments, the condition is cancer. In some embodiments, the cancer is Renal Cell Carcinoma, glioblastoma, glioma, such as low-grade glioma, Non-Hodgkin Lymphoma (NHL), Hodgkin's Disease (HD), Waldenstrom's macroglobulinemia, Acute Myeloid Leukemia, Multiple Myeloma, diffuse large cell lymphoma, follicular lymphoma, or Non-Small Cell Lung Cancer.

[0082] In another aspect, the description provides a method of inhibiting tumor growth or progression in a subject who has malignant cells expressing CD70, comprising administering to the subject in need an effective amount of a pharmaceutical composition comprising a manipulated immune cell, as described in this document, to the subject.

[0083] In another aspect, the description provides a method of inhibiting metastasis of malignant cells expressing CD70 in a subject, comprising administering to the subject in need an effective amount of a pharmaceutical composition comprising a manipulated immune cell, as described in this document, to the subject.

[0084] In another aspect, the description provides a method of induction Petition 870260028237, dated 03 / 25 / 2026, pages 842 / 1082 22 / 230 zir tumor regression in a subject who has malignant cells expressing CD70, comprising administering to the subject in need an effective amount of a pharmaceutical composition comprising a manipulated immune cell, as described in this document, to the subject.

[0085] In some embodiments, any of the above methods also includes administering one or more additional therapies, such as, for example, a monoclonal antibody and / or a chemotherapeutic agent. In some embodiments, the monoclonal antibody may be, for example, an antibody that binds to a checkpoint inhibitor, such as, for example, an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, any of the above methods also includes administering a Tyrosine Kinase Receptor inhibitor such as sunitinib or axitinib.

[0086] In some embodiments, the description provides a specific CAR for CD70 comprising an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular domain comprises a single-chain Fv fragment (scFv) binding to the CD70 extracellular domain with a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises an amino acid sequence that shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 18 and the VL region comprises an amino acid sequence that shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 17; or the VH region comprises an amino acid sequence that shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 34 and the VL region comprises an amino acid sequence that shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 33. Petition 870260028237, dated 03 / 25 / 2026, p. 843 / 1082 23 / 230

[0087] In some embodiments, the extracellular domain comprises an amino acid sequence that shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 319. In some embodiments, the extracellular domain comprises an amino acid sequence that shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 327.

[0088] In some embodiments, the description provides a polynucleotide encoding a specific CAR for CD70, wherein the polynucleotide comprises a nucleic acid sequence that shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 297 and shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 298; or shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 307 and shares at least 95%, 96%, 97%, 98%, 99%, or 100% with SEQ ID NO: 308.

[0089] In some embodiments, the description provides a CAR comprising an antigen-binding molecule that specifically binds to CD70, wherein the antigen-binding molecule comprises at least one of: a variable heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 49-51, 55-57, 61-63, 67-69, 73-75, 79-81, 85-87, 91-93, 97-99, 103-105, 109-111, 115-117, 121-123, 127-129, 133-135, 139-141, 145-147, 151-153, 157-159, 163-165, 169-171, 175-177, 181-183, 187-189, 382-384, 388-390, 394-396, 400-402, 406-408, 412-414, 418-420, 424-426, 430-432, 436-438, 442-444, 448-450, 454-456, 460-462, 466-468, 472-474, 478-480, 484-486, 490-492, 496-498, 502-504 and 508-510;a variable heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ NOS 52, 53, 58, 59, 64, 65, 70, 71, 76, 77, 82, 83, 88, 89, 94, 95, 100, 101, 106, 107, 112, 113, 118, 119, 124, 125, 130, 131, 136, 137, 142, 143, 148, 149, 154, 155, 160; Petition 870260028237, dated 03 / 25 / 2026, pp. 844 / 1082 24 / 230 161, 166, 167, 172, 173, 178, 179, 184, 185, 190, 191, 385, 386, 391, 392, 397, 398, 403, 404, 409, 410, 415, 416, 421, 422, 427, 428, 433, 434, 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 482, 487, 488, 493, 494, 499, 500, 505, 506, 511 and 512; one Variable heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOS 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 387, 393, 399, 405, 411, 417, 423, 429, 435, 441, 447, 453, 459, 465, 471, 477, 483, 489,495, 501, 507 and 513; a variable light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ NOs: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226, 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262, 514, 517, 520, 523, 526, 529, 532, 535, 538, 541, 544, 547, 550, 553, 556, 559, 562, 565, 568, 571, 574 and 577; a variable light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs. 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245, 248, 251, 254, 257, 260, 263, 515, 518, 521, 524, 527, 530, 533, 536, 539, 542, 545, 548, 551, 554, 557, 560, 563, 566, 569, 572, 575 and 578; a variable light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOS. 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237, 240, 243, 246, 249, 252, 255, 258, 261, 264, 516, 519, 522, 525, 528, 531, 534, 537, 540, 543, 546, 549, 552, 555, 558, 561, 564, 567, 570, 573, 576 and 579.

[0090] In some embodiments, the antigen-binding molecule comprises a variable heavy chain domain comprising amino acid sequences for CDRH1, CDRH2, and CDRH3, respectively, selected from one of the SEQ ID NOs: 49-51, Petition 870260028237, dated 03 / 25 / 2026, p. 845 / 1082 25 / 230 52-53, 54; 55-57, 58-59, 60; 61-63, 64-65, 66; 67-69, 70-71, 72; 73-75, 76-77, 78; 79-81, 82-83, 84; 85-87, 88-89, 90; 91-93, 94-95, 96; 97-99, 100-101, 102; 103-105, 106-107, 108; 109-111, 112-113, 114; 115-117, 118-119, 120; 121-123, 124-125, 126; 127-129, 130-131, 132; 133-135, 136-137, 138; 139-141, 142-143, 144; 145-147, 148-149, 150; 151-153, 154-155, 156; 157-159, 160-161, 162; 163-165, 166-167, 168; 169-171, 172-173, 174; 175-177, 178-179, 180; 181-183, 184-185, 186; 187-189, 190-191, 192; 382-384, 385-386, 387; 388-390, 391-392, 393; 394-396, 397-398, 399; 400-402, 403-404, 405; 406-408, 409-410, 411; 412-414, 415-416, 417; 418-420, 421-422, 423; 424-426, 427-428, 429; 430-432, 433-434, 435; 436-438, 439, 440, 441; 442-444, 445-446, 447; 448-450, 451-452, 453; 454-456, 457-458, 459; 460-462, 463-464, 465; 466-468, 469-470, 471; 472-474, 475-476, 477; 478-480, 481-482, 483; 484-486, 487-488, 489; 490-492, 493-494, 495; 496-498, 499-500, 501; 502-504, 505-506, 507; or 508-510, 511-512, 513; and a variable light chain domain comprising amino acid sequences for CDRL1, CDRL2, and CDRL3, respectively, selected from one of the following SEQ ID NOs: 193, 194, 195; 196, 197, 198; 199, 200, 201; 202, 203, 204; 205, 206, 207; 208, 209, 210; 211, 212, 213; 214, 215, 216; 217, 218, 219; 220, 221, 222; 223, 224, 225; 226, 227, 228; 229, 230, 231; 232, 233, 234; 235, 236, 237; 238, 239, 240; 241, 242, 243; 244, 245, 246; 247, 248, 249; 250, 251, 252; 253, 254, 255; 256, 257, 258; 259, 260, 261; 262, 263, 264; 514, 515, 516; 517, 518, 519; 520, 521, 522; 523, 524, 525; 526, 527, 528; 529, 530, 531; 532, 533, 534; 535, 536, 537; 538, 539, 540; 541, 542, 543; 544, 545, 546; 547, 548, 549; 550, 551, 552; 553, 554, 555; 556, 557, 558; 559, 560, 561; 562, 563, 564; 565, 566, 567; 568, 569, 570; 571, 572, 573; 574, 575, 576; and 577, 578, 579.

[0091] In some embodiments, the antigen-binding molecule comprises amino acid sequences for CDRH1, CDRH2, Petition 870260028237, dated 03 / 25 / 2026, p. 846 / 1082 26 / 230 CDRH3, CDRL1, CDRL2 and CDRL3, respectively, selected from one of the SEQ IDs 49-51, 52-53, 54, 193, 194, 195; 55-57, 58-59, 60, 196, 197, 198; 61-63, 64-65, 66, 199, 200, 201; 67-69, 70-71, 72, 202, 203, 204; 73-75, 76-77, 78, 205, 206, 207; 79-81, 82-83, 84, 208, 209, 210; 85-87, 88-89, 90, 211, 212, 213; 91-93, 94-95, 96, 214, 215, 216; 97-99, 100-101, 102, 217, 218, 219; 103-105, 106-107, 108, 220, 221, 222; 109-111, 112-113, 114, 223, 224, 225; 115-117, 118-119, 120, 226, 227, 228; 121-123, 124-125, 126, 229, 230, 231; 127-129, 130-131, 132, 232, 233, 234; 133-135, 136-137, 138, 235, 236, 237; 139-141, 142-143, 144, 238, 239, 240; 145-147, 148-149, 150, 241, 242, 243; 151-153, 154-155, 156, 244, 245, 246; 157-159, 160-161, 162, 247, 248, 249; 163-165, 166-167, 168, 250, 251, 252; 169-171, 172-173, 174, 253, 254, 255; 175-177, 178-179, 180, 256, 257, 258; 181-183, 184-185, 186, 259, 260, 261; 187-189, 190-191, 192, 262, 263, 264; 382-384, 385-386, 387, 514, 515, 516;388-390, 391-392, 393, 517, 518, 519; 394-396, 397-398, 399, 520, 521, 522; 400-402, 403-404, 405, 523, 524, 525; 406-408, 409-410, 411, 526, 527, 528; 412-414, 415-416, 417, 529, 530, 531; 418-420, 421-422, 423, 532, 533, 534; 424-426, 427-428, 429, 535, 536, 537; 430-432, 433-434, 435, 538, 539, 540; 436-438, 439-440, 441, 541, 542, 543; 442-444, 445-446, 447, 544, 545, 546; 448-450, 451-452, 453, 547, 548, 549; 454-456, 457-458, 459, 550, 551, 552; 460-462, 463-464, 465, 553, 554, 555; 466-468, 469-470, 471, 556, 557, 558; 472-474, 475-476, 477, 559, 560, 561; 478-480, 481-482, 483, 562, 563, 564; 484-486, 487-488, 489, 565, 566, 567; 490-492, 493-494, 495, 568, 569, 570; 496-498, 499-500, 501, 571, 572, 573; 502-504, 505-506, 507, 574, 575, 576; and 508-510, 511-512, 513, 577, 578, 579.

[0092] In some embodiments, the antigen-binding molecule comprises a variable light chain domain comprising amino acid sequences for CDRH1, CDRH2 and CDRH3, respectively. Petition 870260028237, dated 03 / 25 / 2026, page 847 / 1082 27 / 230 specifically, selected from one of the SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 and 380; and a variable heavy chain domain comprising amino acid sequences for CDRL1, CDRL2 and CDRH3, respectively, selected from one of the following SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 and 381.

[0093] In some embodiments, the antigen-binding molecule comprises amino acid sequences for variable light chain domain and variable heavy chain domain, respectively, selected from one of the following SEQ ID NOs: 1 and 2; 3 and 4; 5 and 6; 7 and 8; 9 and 10; 11 and 12; 13 and 14; 15 and 16; 17 and 18; 19 and 20; 21 and 22; 23 and 24; 25 and 26; 27 and 28; 29 and 30; 31 and 32; 33 and 34; 35 and 36; 37 and 38; 39 and 40; 41 and 42; 43 and 44; 45 and 46; 47 and 48; 338 and 339; 340 and 341; 342 and 343; 344 and 345; 346 and 347; 348 and 349; 350 and 351; 352 and 353; 354 and 355; 356 and 357; 358 and 359; 360 and 361; 362 and 363; 364 and 365; 366 and 367; 368 and 369; 370 and 371; 372 and 373; 374 and 375; 376 and 377; 378 and 379; and 380 and 381.

[0094] In another aspect, the description provides antibodies that bind specifically to Cluster of Differentiation 70 (CD70).

[0095] In some embodiments, the antibody comprises a VH region indicated in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381; and / or a VL region indicated in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, Petition 870260028237, dated 03 / 25 / 2026, pages 848 / 1082 28 / 230 661, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380.

[0096] In some embodiments, the antibody comprises a variable heavy chain (VH) region comprising (i) a VH CDR1 comprising the sequence indicated in SEQ ID NO: 49, 50, 51, 55, 56, 57, 61, 62, 63, 67, 68, 69, 73, 74, 75, 79, 80, 81, 85, 86, 87, 91, 92, 93, 97, 98, 99, 103, 104, 105, 109, 110, 111, 115, 116, 117, 121, 122, 123, 127, 128, 129, 133, 134, 135, 139, 140, 141, 145, 146, 147, 151, 152, 153, 157, 158, 159, 163, 164, 165, 169, 170, 171, 175, 176, 177, 181, 182, 183, 187, 188, 189, 382, ​​383, 384, 388, 389, 390, 394, 395, 396, 400, 401, 402, 406, 407, 408, 412, 413, 414, 418, 419, 420, 424, 425, 426, 430, 431, 432, 663, 664, 665, 436, 437, 438, 442, 443, 444, 448, 449, 450, 454, 455, 456, 460, 461, 462, 466, 467, 468, 472, 473, 474, 478, 479, 480, 484, 485, 486, 490, 491, 492, 496, 497, 498, 502, 503, 504, 508, 509 or 510; (ii) a VH CDR2 comprising the sequence indicated in SEQ ID NO: 52, 53, 58, 59, 64, 65, 70, 71, 76, 77, 82, 83, 88, 89, 94, 95, 100, 101, 106, 107, 112, 113, 118, 119, 124, 125, 130, 131, 136, 137, 142, 143, 148, 149, 154, 155, 160, 161, 166, 167, 172, 173, 178, 179, 184, 185, 190, 191, 385, 386, 391, 392, 397, 398, 403, 404, 409, 410, 415, 416, 421, 422, 427, 428, 433, 434, 666, 667, 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 482, 487, 488, 493, 494, 499, 500, 505, 506, 511 or 512; and iii) a VH CDR3 comprising the sequence indicated in SEQ ID NO: 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 387, 393, 399, 405, 411, 417, 423, 429, 435, 668, 441, 447, 453, 459, 465, 471, 477, 483, 489, 495, 501, 507 or 513; and / or a variable light chain (VL) region comprising (i) a CDR1 VL comprising the sequence indicated in SEQ ID NO: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226, 229, 232, 235, 238, 241, 244, 247, 250, 253, Petition 870260028237, dated 03 / 25 / 2026, pp. 849 / 1082 29 / 230 256, 259, 262, 514, 517, 520, 523, 526, 529, 532, 535, 538, 669, 541, 544, 547, 550, 553, 556, 559, 562, 565, 568, 571, 574 or 577; (ii) a VL CDR2 comprising the sequence indicated in SEQ ID NO:194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245, 248, 251, 254, 257, 260, 263, 515, 518, 521, 524, 527, 530, 533, 536, 539, 670, 542, 545, 548, 551, 554, 557, 560, 563, 566, 569, 572, 575 or 578; and (iii) a VL CDR3 comprising the sequence indicated in SEQ ID NO: 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237, 240, 243, 246, 249, 252, 255, 258, 261, 264, 516, 519, 522, 525, 528, 531, 534, 537, 540, 671, 543, 546, 549, 552, 555, 558, 561, 564, 567, 570, 573, 576 or 579.

[0097] In some embodiments, the antibody comprises a VH region comprising a VH CDR1, VH CDR2 and VH CDR3 of the VH sequence indicated in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381; and / or a VL region comprising VL CDR1, VL CDR2 and VL CDR3 of the sequence indicated in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 661, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380.

[0098] In other aspects, the description provides nucleic acids, vectors, host cells, pharmaceutical compositions, manufacturing methods, and methods of treating conditions with the disclosed antibodies. BRIEF DESCRIPTION OF THE FIGURES

[0099] FIG. 1 is a graph showing volumes of 1 tumor from mice treated with different doses of 4F11 CAR T cells in a subcutaneous xenograft model.

[0100] FIG. 2 is a graph showing body weights of ca Petition 870260028237, dated 03 / 25 / 2026, pp. 850 / 1082 30 / 230 mice treated with different doses of CAR T 4F11 cells in a subcutaneous xenograft model.

[0101] FIG. 3 is a graph showing tumor volumes of mice treated with CAR T 4F11 and P08F08 with or without CD70 KO in a subcutaneous xenograft model.

[0102] FIG. 4 is a graph showing body weights of mice treated with CAR T 4F11 and P08F08 with or without CD70 KO in a subcutaneous xenograft model.

[0103] FIGS. 5A-5C are a series of graphs showing tumor flux values ​​from mice treated with control cells, cells expressing CAR 4F11 with or without CD70 KO and with or without TCRa KO, and mice treated with cells expressing CAR P08F08 with or without CD70 KO and with or without TCRa KO, in 3 donors in the ACHN lung metastasis model.

[0104] FIG. 5A shows results obtained with control cells, cells expressing CAR 4F11 with CD70, TCRa or CD70 and TCR KOs and cells expressing CAR P08F08 with TCR KO; the cells were obtained from Donor D419.

[0105] FIG. 5B shows results obtained with control cells, cells expressing CAR 4F11 with or without CD70 KO, and cells expressing CAR P08F08; the cells were obtained from Donor D710.

[0106] FIG. 5C shows results obtained with control cells, cells expressing CAR 4F11 with or without CD70 KO, and cells expressing CAR P08F08; the cells were obtained from Donor D503.

[0107] FIGS. 6A-6F show five exemplary and non-limiting CAR designs. In each of FIGS. 6A-6F, an approximate distance from the antigen-binding fragment of the CD70-specific domain to the cell membrane is indicated by a double arrow. Petition 870260028237, dated 03 / 25 / 2026, pp. 851 / 1082 31 / 230 is marked with the number of amino acid (aa) residues between scFv and the transmembrane domain.

[0108] FIG. 6A shows a second-generation CAR design including an extracellular domain comprising a CD70-specific scFv, a hinge, a transmembrane domain, a first intracellular domain (a 4-1BB domain) and a second intracellular domain (a CD3Z signaling domain).

[0109] FIG. 6B shows the CAR SR2 format in which a suicide switch is created by inserting two RTX epitopes (i.e., CD20 epitopes) between the hinge and scFv.

[0110] FIG. 6C shows the CAR RSRQR format, which adds a third RTX epitope and the CD34 epitope.

[0111] FIG. 6D shows the RSR format, in which two epitopes RTX flanks scFv.

[0112] FIG. 6E shows a modification of the CAR RSR format in which the hinge domain is shortened (called RSR-short).

[0113] FIG. 6F shows the CAR R2S format, in which the two RTX epitopes of the CAR R2 format are moved to N-terminal for scFv.

[0114] FIG. 7 shows the viability of target cells after exposure to CD70-specific CARs in four formats or non-transfected control cells (NTD).

[0115] FIGS. 8A-8D are a series of graphs showing cell death of 786-0, ACHN or REH cells using CD70-specific CAR T cells where the extracellular domain of CAR comprises the scFvs indicated in the legend in FIG. 8D.

[0116] FIG. 8A shows the 786-0 cell death, in which the extracellular domain of CAR comprises the scFvs indicated in the legend shown in FIG. 8D.

[0117] FIG. 8B shows the cell death of ACHN, in which the Petition 870260028237, dated 03 / 25 / 2026, pages 852 / 1082 32 / 230 extracellular minimum of CAR comprises the scFvs indicated in the legend shown in FIG. 8D.

[0118] FIG. 8C shows REH cell death, where the extracellular domain of CAR comprises the scFvs indicated in the legend shown in FIG. 8D.

[0119] FIGS. 9A-9D are a series of graphs showing the serial killing of 786-0, ACHN or REH cells using CD70-specific CAR T cells where the extracellular domain of CAR comprises the scFvs indicated in the legend in Figure 9D.

[0120] FIG. 9A is a graph showing the efficacy of CD70-specific CARs after repeated exposure to luciferase-labeled 786-O target cells (CAR T cells were transferred to a 96-well plate containing fresh targets every 2-3 days). The E:T ratio was 3:1. CARs were expressed in D503 donor cells.

[0121] FIG. 9B is a graph showing the efficacy of CD70-specific CARs after repeated exposure to luciferase-labeled ACHN target cells (CAR T cells were transferred to a 96-well plate containing fresh targets every 2-3 days). The E:T ratio was 10:1. CARs were expressed in D503 donor cells.

[0122] FIG. 9C is a graph showing the efficacy of CD70-specific CARs after repeated exposure to luciferase-labeled REH target cells (2x106 cells added at the indicated time points). The E:T ratio was 1:5. The CARs were expressed in D503 donor cells.

[0123] FIG. 10 is a series of graphs that shows the effectiveness of Specific CARs for CD70 in R2S, SR2, or RSRQR formats after repeated exposure to luciferase-labeled REH target cells (2x10⁶ cells added at the indicated time points). The ratio Petition 870260028237, dated 03 / 25 / 2026, page 853 / 1082 33 / 230 E:T was 1:5. CARs were expressed in D772 donor cells.

[0124] FIG. 11 is a graph showing tumor flux values ​​from mice treated with control cells or cells expressing various scFvs of CAR in the ACHN lung metastasis model.

[0125] FIGURES 12A-12C are a series of graphs showing the quantification of CD70 expression in terms of CD70 antibody-binding capacity (ABC) in various cell lines tested or cell lines and cells derived from RCC patients. Data from cells derived from RCC patients are also shown.

[0126] FIG. 12A shows the quantification of CD70 expression in terms of CD70 antibody-binding capacity (ABC) in several cell lines tested.

[0127] FIG. 12B shows the quantification of CD70 expression in terms of antibody-binding capacity (ABC) of CD70 cells derived from RCC patients.

[0128] FIG. 12C shows data from cells derived from patients with RCC.

[0129] FIGURES 13A-13C are a series of graphs showing the death of target cells from the patient with RCC WD-59279, patient-derived cell lines or ACHN, and antibody binding capacity is indicated in each panel.

[0130] FIGURES 13A-B show the death of target cells from patients with RCC and the antibody binding capacity.

[0131] FIG. 13C shows the death of target ACHN cells and their ability to bind to the antibody.

[0132] FIGURES 14A-14B are a series of bar graphs showing the quantification of CD70 receptor numbers and heme tumor cell death by CAR 4F11 in QR3 to E:T format. Petition 870260028237, dated 03 / 25 / 2026, pp. 854 / 1082 34 / 230 1:1 for additional cell lines that express CD70 at varying levels.

[0133] FIG. 14A is a bar graph showing the quantification of CD70 receptor numbers from CAR 4F11 in QR3 to E:T 1:1 format for additional cell lines expressing CD70 at varying levels.

[0134] FIG. 14B is a bar graph showing the killing of heme tumor cells by CAR 4F11 in the QR3 format at E:T 1:1 for additional cell lines expressing CD70 at varying levels.

[0135] FIGS. 15A-15B show a series of graphs showing tumor volumes and body weights of mice treated with CAR T 4F11 and P08F08 at 10x106 cell or 5x106 cell dose in a subcutaneous xenograft model.

[0136] FIG. 15A is a graph showing tumor volumes of mice treated with CAR T 4F11 and P08F08 at 10x106 cell or 5x106 cell doses in a subcutaneous xenograft model.

[0137] FIG. 15B is a graph showing the body weights of mice treated with CAR T 4F11 and P08F08 at 10x106 cell or 5x106 cell doses in a subcutaneous xenograft model. DETAILED DESCRIPTION

[0138] The description disclosed in this document provides chimeric antigen receptors (CARs) and immune cells comprising CARs (e.g., CAR-T cells) that specifically bind to CD70 (e.g., human CD70). The description also provides polynucleotides encoding these CARs, the compositions comprising these CAR-T cells, and methods for manufacturing and using these CARs and CAR-T cells. The description also provides methods for treating a condition associated with CD70 expression in a subject, such as cancer. General techniques Petition 870260028237, dated 03 / 25 / 2026, pp. 855 / 1082 35 / 230

[0139] The compositions and methods of the description employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the ability of the technique. Such techniques are fully explained in the literature, such as Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Human Press; Cell Biology: A Laboratory Notebook (JE Cellis, ed., 1998) Academic Press; Animal Cell Culture (RI Freshney, ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-1998); J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D.M. Weir and C.C.)Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller and MP Calos, eds., 1987); Current Protocols in Molecular Biology (FM Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction (Mullis et al., eds., 1994); Current Protocols in Immunology (JE Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty, ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Handbook (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995). Definitions

[0140] The term extracellular ligand-binding domain, as used in this document, refers to an oligo- or polypeptide Petition 870260028237, dated 03 / 25 / 2026, pp. 856 / 1082 36 / 230 which is capable of binding a ligand. In some exemplary embodiments, the domain will be able to interact with a cell surface molecule. For example, the extracellular ligand-binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state.

[0141] The term stalk domain or hinge domain is used interchangeably in this document to refer to any oligo- or polypeptide that has the function of linking the transmembrane domain to the extracellular ligand-binding domain in a CAR. In particular, stalk domains are used to provide more flexibility and accessibility to the extracellular ligand-binding domain.

[0142] The term intracellular signaling domain refers to the portion of a protein that transduces the function signal from the effector signal and directs the cell to perform a specialized function.

[0143] A costimulatory molecule, as used in this document, refers to the cognate binding partner on an immune cell, for example, a T cell, that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response by the cell, such as, but not limited to, proliferation. Costimulatory molecules include, among others, an MHC class I molecule, BTLA, and Toll-linked receptor ligand. Examples of costimulatory molecules include CD27, CD28, CD8, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds to CD83 and similar molecules.

[0144] A costimulatory ligand refers to a molecule on an antigen-presenting cell that specifically binds to a cognate costimulatory signaling molecule on an immune cell, for example, a T cell, thus providing a signal that, in addition to the signal Petition 870260028237, dated 03 / 25 / 2026, page 857 / 1082 37 / 230 primary provided, for example, by the binding of a TCR / CD3 complex to a peptide-laden MHC molecule, mediates a T cell response, including, among others, proliferation, activation, differentiation and the like. A costimulatory ligand may include, among others, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD-L2, 4-1BBL, OX40L, inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, M1CB, HVEM, lymphotoxin β receptor, 3 / TR6, ILT3, ILT4, an agonist or antibody that binds to the Toll ligand receptor, and a ligand that binds specifically to B7-H3. A costimulatory ligand also includes, inter alia, an antibody that binds specifically to a costimulatory molecule present on a T cell, such as, among others, CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, antigen1 associated with lymphocyte function (LFA-1), CD2, CD7, LTGHT, NKG2C, B7-H3, a ligand that binds specifically to CD83.

[0145] An antibody is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used in this document, the term encompasses not only intact monoclonal or polyclonal antibodies, but also their binding fragments (such as Fab, Fab', F(ab')2, Fv), single-chain antibodies (scFv) and domain antibodies (including, for example, shark and camelid antibodies), and fusion proteins comprising an antibody, and any other modified configuration of the immunoglobulin molecule comprising an antigen recognition site. An antibody includes an antibody of any class, such as IgG, IgA or IgE, IgD or IgM (or subclasses thereof), and the antibody need not be of any particular class. Depending on the amino acid sequence of the antibody in the constant region Petition 870260028237, dated 03 / 25 / 2026, pages 858 / 1082 Due to the 38 / 230 of their heavy chains, immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant regions of the heavy chain that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0146] The term antigen-binding fragment or antigen-binding portion of an antibody, as used in this document, refers to one or more fragments of an intact antibody that retain the ability to bind specifically to a given antigen (e.g., CD70). The antigen-binding functions of an antibody can be performed by fragments of an intact antibody. Examples of binding fragments encompassed within the term antigen-binding fragment of an antibody include Fab; Fab'; F(ab')2; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a single-domain antibody fragment (dAb) (Ward et al., Nature 341:544-546, 1989) and an isolated complementarity-determining region (CDR).

[0147] An antibody, an antigen-binding fragment, an antibody conjugate, or a polypeptide that binds preferentially or specifically (used interchangeably in this document) to a target (e.g., the CD70 protein) is a well-understood term in the art, and the methods for determining such specific or preferential binding are also well known in the art. A molecule is said to exhibit specific or preferential binding if it reacts or associates more frequently, more rapidly Petition 870260028237, dated 03 / 25 / 2026, p. 859 / 1082 39 / 230 specifically, with greater duration and / or greater affinity to a specific cell or substance than to alternative cells or substances. An antibody binds specifically or preferentially to a target if it binds with greater affinity, avidity, more readily, and / or for a longer duration than it binds to other substances. For example, an antibody that binds specifically or preferentially to a CD70 epitope is an antibody that binds to this epitope with greater affinity, avidity, more readily, and / or for a longer duration than it binds to other CD70 epitopes or non-CD70 epitopes. It is also understood, when reading this definition, for example, that an antibody (or a fraction or epitope) that binds specifically or preferentially to a first target may or may not bind specifically or preferentially to a second target. Thus, specific or preferential binding does not necessarily require (although it may include) exclusive binding.Generally, but not necessarily, reference to the link means preferred link.

[0148] A variable region of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four major structure regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are joined in close proximity to the FRs and, with the CDRs of the other chain, contribute to the formation of the antibody antigen-binding site. There are at least two techniques for determining CDRs: (1) a cross-species sequence variability-based approach (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, 5th ed., 1991, National Institutes of Health, Bethesda MD); and (2) a cross-species sequence variability-based approach. Petition 870260028237, dated 03 / 25 / 2026, pp. 860 / 1082 40 / 230 crystallographic representations of antigen-antibody complexes (Al-lazikani et al., 1997, J. Molec. Biol. 273:927-948). As used in this document, a CDR may refer to CDRs defined by either approach or by a combination of both approaches.

[0149] A variable domain CDR is a set of amino acid residues within the variable region that are identified according to the definitions of Kabat, Chothia, the Kabat and Chothia accumulation, AbM, contact and / or conformational definitions, or any method of CDR determination known in the art. Antibody CDRs can be identified as hypervariable regions originally defined by Kabat et al. See, for example, Kabat et al., 1992, Sequence of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington DC. The positions of CDRs can also be identified as the structural loop structures originally described by Chothia and others. See, for example, Chothia et al., Nature 342:877-883, 1989.Other approaches to CDR identification include the AbM definition, which is a middle ground between Kabat and Chothia and is derived using Oxford Molecular's AbM antibody modeling software (now Accelrys®), or the contact definition of CDRs based on observed antigen contacts, as established in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another approach, referred to in this document as the conformational definition of CDRs, the positions of CDRs can be identified as the residues that make enthalpic contributions to antigen binding. See, for example, Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. Still other definitions of CDR limits may not strictly follow one of the above approaches, but will nevertheless overlap with at least a portion of Kabat's CDRs, although they may be reduced or expanded in light of predictions or experimental findings regarding residuals or groups of... Petition 870260028237, dated 03 / 25 / 2026, pp. 861 / 1082 41 / 230 specific residues or even total CDRs do not significantly impact antigen binding. As used in this document, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used in this document may utilize CDRs defined according to any of these approaches. For any specific modality containing more than one CDR, the CDRs may be defined according to any of the Kabat, Chothia, extended, AbM, contact, and / or conformal definitions.

[0150] As used in this document, monoclonal antibody refers to an antibody obtained from a substantially homogeneous population of antibodies, that is, the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in small quantities. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The monoclonal modifier indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be interpreted as requiring the production of the antibody by any specific method.For example, the monoclonal antibodies to be used according to the description can be made by the hybridoma method first described by Kohler and Milstein, Nature 256:495, 1975, or they can be made by recombinant DNA methods, as described in US Pat. No. 4,816,567. Monoclonal antibodies can also be isolated from phage libraries generated using the techniques described in McCafferty et al., Nature 348: 552-554, 1990, for example. Petition 870260028237, dated 03 / 25 / 2026, p. 862 / 1082 42 / 230

[0151] As used in this document, humanized antibody refers to forms of non-human antibodies (e.g., murine) that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab')2, or other antibody antigen-binding subsequences) containing a minimal sequence derived from non-human immunoglobulin. In some exemplary embodiments, humanized antibodies are human immunoglobulins (recipient antibody) in which residues of a recipient complementarity-determining region (CDR) are replaced by residues of a CDR from a non-human species (donor antibody), such as mouse, rat, or rabbit, with the desired specificity, affinity, and capability. In some cases, residues of the Fv (FR) core structure region of human immunoglobulin are replaced by corresponding non-human residues.Furthermore, the humanized antibody may comprise residues that are not found in the recipient antibody, nor in the imported CDR or mainframe sequences, but are included to further refine and optimize antibody performance. In general, the humanized antibody will comprise substantially at least one, and typically two, variable domains, wherein all or substantially all CDR regions correspond to those of a non-human immunoglobulin and all or substantially all FR regions are those of a consensus sequence of the human immunoglobulin. The humanized antibody will also ideally comprise at least a portion of an immunoglobulin constant (Fc) region or domain, typically from a human immunoglobulin. Antibodies with modified Fc regions, as described in WO 99 / 58572, are exemplary embodiments.Other forms of humanized antibodies have one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, or CDR H3) that are altered relative to the anti-antibody. Petition 870260028237, dated 03 / 25 / 2026, p. 863 / 1082 43 / 230 original body, which are also called one or more CDRs derived from one or more CDRs of the original antibody.

[0152] As used in this document, human antibody means an antibody with an amino acid sequence corresponding to that of an antibody produced by a human and / or that has been made using any of the techniques for producing human antibodies known to those skilled in the art or disclosed in this document. This definition of a human antibody includes antibodies comprising at least one human heavy chain polypeptide or at least one human light chain polypeptide. One such example is an antibody comprising murine light chain and human heavy chain polypeptides. Human antibodies can be produced using various techniques known in the art. In some embodiments, the human antibody is selected from a phage library, wherein the phage library expresses human antibodies (Vaughan et al., Nature Biotechnology, 14:309-314, 1996; Sheets et al., Proc. Natl. Acad. Sci.(USA) 95:61576162, 1998; Hoogenboom and Winter, J. Mol. Biol., 227:381, 1991; Marks et al., J. Mol. Biol., 222:581, 1991). Human antibodies can also be produced by immunizing animals in which human immunoglobulin loci have been transgenically introduced in place of endogenous loci, for example, mice in which endogenous immunoglobulin genes have been partially or completely disrupted or inactivated. This approach is described in US Patents Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016. Alternatively, human antibody can be prepared by immortalizing human B lymphocytes that produce an antibody directed against a target antigen (such B lymphocytes can be recovered from an individual or from single cell cDNA cloning or may have been immunized in vitro). See, for example, Cole et al. Monoclonal. Petition 870260028237, dated 03 / 25 / 2026, p. 864 / 1082 44 / 230 Antibodies and Cancer Therapy, Alan R. Liss, p. 77, 1985; Boerner et al., J. Immunol., 147 (1):86-95, 1991; and Pat. US No. 5,750,373.

[0153] The term chimeric antibody is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from other species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

[0154] The terms polypeptide, oligopeptide, peptide, and protein are used interchangeably in this document to refer to amino acid chains of any length—in some embodiments, relatively short (e.g., 10–100 amino acids). The chain may be linear or branched, may comprise modified amino acids, and / or may be interrupted by non-amino acids. The terms also encompass an amino acid chain that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included in the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, non-natural amino acids, etc.), as well as other modifications known in the art. It is understood that polypeptides may occur as single chains or associated chains.

[0155] A monovalent antibody comprises one antigen-binding site per molecule (e.g., IgG or Fab). In some cases, a monovalent antibody may have more than one antigen-binding site, but the binding sites are for different antigens.

[0156] A bivalent antibody comprises two antigen-binding sites per molecule (e.g., IgG). In some cases, the two binding sites have the same antigen specificities. In Petition 870260028237, dated 03 / 25 / 2026, p. 865 / 1082 45 / 230 However, bivalent antibodies can be bispecific.

[0157] The antibodies described can be produced using techniques well known in the art, for example, recombinant technologies, phage display technologies, synthetic technologies, or combinations of these technologies or other technologies readily known in the art (see, for example, Jayasena, SD, Clin. Chem., 45: 1628-50, 1999 and Fellouse, FA, et al, J. MoI. Biol., 373(4):924-40, 2007).

[0158] As known in the art, polynucleotide or nucleic acid, as used interchangeably in this document, refers to chains of nucleotides of any length and includes DNA and RNA. Nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases and / or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, the modification in the nucleotide structure may be transmitted before or after chain assembly. The nucleotide sequence may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, as well as by conjugation with a labeling component.Other types of modifications include, for example, caps, replacement of one or more of the naturally occurring nucleotides with an analogous modification, or internucleotide, such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.). Petition 870260028237, dated 03 / 25 / 2026, pp. 866 / 1082 46 / 230 those containing chelating agents (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylating agents, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Furthermore, any of the hydroxyl groups normally present in sugars can be substituted, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages with additional nucleotides, or can be conjugated to solid supports. Terminal OH at 5' and 3' can be phosphorylated or substituted by amines or organic termination group fractions of 1 to 20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups.Polynucleotides may also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, alpha or beta-anomeric sugars, epimeric sugars such as arabinose, xyloses or lycoses, pyranose sugars, furanose sugars, sedo-heptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester bonds may be replaced by alternative linking groups. These alternative linkage groups include, among others, embodiments in which phosphate is replaced by P(O)S(thioate), P(S)S (dithioate), (O)NR2 (amidate), P(O)R, P(O)OR', CO or CH2 (formacetal), wherein each R or R' is independently H or alkyl substituted or unsubstituted (1-20 C), optionally containing an ether (-O-), aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl linkage.Not all bonds in a polynucleotide need to be identical. The preceding description applies to all polynucleotides referred to in this document, including RNA and DNA.

[0159] As is known in the art, a constant region of. Petition 870260028237, dated 03 / 25 / 2026, p. 867 / 1082 47 / 230 an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, alone or in combination.

[0160] As used in this document, substantially pure refers to material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, and at least 99% pure.

[0161] A host cell includes an individual cell or cell culture that may be a recipient or that has received vector(s) for the incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original cell by virtue of natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with polynucleotides of this description.

[0162] As used in this document, immune cell refers to a cell of hematopoietic origin functionally involved in the initiation and / or execution of innate and / or adaptive immune responses.

[0163] As known in the art, the term Fc region is used to define a C-terminal region of an immunoglobulin heavy chain. The Fc region can be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the Fc region of the human IgG heavy chain is generally defined to extend from an amino acid residue at the Cys226 position, or from Pro230, to the carboxyl terminus thereof. The numbering of residues in the Fc region is that of the EU index as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The Fc region of an immunoglobulin generally comprises two constant regions, CH2 and CH3. Petition 870260028237, dated 03 / 25 / 2026, pages 868 / 1082 48 / 230

[0164] As used in the technique, Fc receptor and FcR describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR is a native sequence human FcR. Additionally, in some embodiments, the FcR is one that binds to an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcyRII receptors include FcyRIIA (an activating receptor) and FcyRIIB (an inhibiting receptor), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. FcRs are analyzed in Ravetch and Kinet, Ann. Rev. Immunol., 9:457-92, 1991; Capel et al., Immunomethods, 4:2534, 1994; and de Haas et al., J. Lab. Clin. Med., 126:330-41, 1995. FcR also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol., 117:587, 1976; and Kim et al., J. Immunol., 24:249, 1994).

[0165] The term compete, as used in this document in relation to an antibody, means that a first antibody, or an antigen-binding fragment (or portion thereof), binds to an epitope in a manner sufficiently similar to the binding of a second antibody, or an antigen-binding portion thereof, such that the binding of the first antibody to its cognate epitope is detectably reduced in the presence of the second antibody compared with the binding of the first antibody in the absence of the second antibody. Alternatively, where the binding of the second antibody to its epitope is also detectably reduced in the presence of the first antibody, may, but need not, be the case. That is, a first antibody may inhibit the binding of a second antibody to its epitope without the second antibody inhibiting the binding of the first antibody to its respective epitope.However, if each antibody detectably inhibits the binding of the other antibody to its epitope. Petition 870260028237, dated 03 / 25 / 2026, p. 869 / 1082 49 / 230 cognate or linker, to an equal, greater or lesser extent, antibodies are said to cross-compete with each other for binding to their respective epitopes. Both competing and cross-competing antibodies are covered by the present invention. Regardless of the mechanism by which this competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope, or a portion thereof), those skilled in the art would appreciate, based on the teachings provided in this document, that such competing and / or cross-competing antibodies are covered and may be useful for the methods disclosed in this document.

[0166] As used in this document, autologous means that cells, a cell line or population of cells used to treat patients originate from the patient in question.

[0167] As used in this document, allogeneic means that cells or a population of cells used to treat patients do not originate from the patient in question, but from a donor.

[0168] As used in this document, treatment is an approach to achieving beneficial or desired clinical outcomes. For the purposes of this description, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cells, inhibiting metastasis of neoplastic cells, shrinking or decreasing the size of a CD70-expressing tumor, such as renal cell carcinoma (RCC), lymphoma, leukemia, or glioma, remission of a CD70-associated disease (e.g., cancer), decreasing symptoms resulting from a CD70-associated disease (e.g., cancer), improving the quality of life of someone suffering from a CD70-associated disease (e.g., cancer), decreasing the dose of other medications needed to treat a CD70-associated disease (e.g., Petition 870260028237, dated 03 / 25 / 2026, pp. 870 / 1082 50 / 230 cancer), to slow the progression of a CD70-associated disease (e.g., cancer), to cure a CD70-associated disease (e.g., cancer), and / or to prolong the survival of patients with a CD70-associated disease (e.g., cancer).

[0169] Improvement refers to the decrease or improvement of one or more symptoms compared to not administering CD70-specific CAR or CD70-specific CAR-T cells. Improvement also includes shortening or reduction in the duration of a symptom.

[0170] As used in this document, an effective dosage or effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired outcomes. For prophylactic use, beneficial or desired outcomes include eliminating or reducing the risk, decreasing the severity, or delaying the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presented during disease development. For therapeutic use, beneficial or desired outcomes include clinical outcomes such as reducing the incidence or improving one or more symptoms of various diseases or conditions associated with CD70 (such as, for example, multiple myeloma), decreasing the dose of other medications needed to treat the disease, potentiating the effect of another medication, and / or delaying the progression of CD70-associated disease in patients.An effective dosage may be administered in one or more doses. For the purposes of this description, an effective dosage of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve prophylactic or therapeutic treatment, directly or indirectly. As understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an effective dosage may be considered in the context of... Petition 870260028237, dated 03 / 25 / 2026, pp. 871 / 1082 51 / 230 text of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective quantity if, in conjunction with one or more other agents, a desirable result can be or is achieved.

[0171] An individual, patient, or subject is a mammal in some modalities, a human being. Mammals include, among others, human beings, monkeys, pigs and other farm animals, sport animals, pets, primates, horses, dogs, cats, rodents including mice, rats, guinea pigs, etc. A subject is a mammal, and the terms are used interchangeably in this document. In some modalities, the subject is a human being. In some modalities, the subject is a non-human primate. In some modalities, the subject is a human being or a monkey, for example, a cynomolgus monkey.

[0172] As used in this document, vector means a construct that is capable of delivering and, in some embodiments, expressing one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

[0173] As used in this document, expression control sequence means a nucleic acid sequence that directs the transcription of a nucleic acid. An expression control sequence can be a promoter, such as a constitutive or inducible promoter, or an enhancer. The expression control sequence is operationally linked to the nucleic acid sequence to be transcribed.

[0174] As used in this document, pharmaceutical carrier Petition 870260028237, dated 03 / 25 / 2026, pages 872 / 1082 52 / 230 An acceptable pharmaceutical excipient includes any material that, when combined with an active ingredient, allows the ingredient to retain biological activity and be non-reactive with the subject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions such as oil-in-water emulsion, and various types of wetting agents. Exemplary diluents for aerosol or parenteral administration are phosphate-buffered saline (PBS) or normal saline (0.9%). Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy, 21st ed., Mack Publishing, 2005).

[0175] The term kon, as used in this document, refers to the association rate constant of an antibody or scFv or CAR to an antigen.

[0176] The term koff, as used in this document, refers to the dissociation rate constant of an antibody or scFv or CAR of the antibody / antigen complex.

[0177] The term Kd, as used in this document, refers to the equilibrium dissociation constant of an antibody-antigen or scFv-antigen or CAR-antigen interaction.

[0178] Reference to about a value or parameter in this document includes (and describes) modalities that are directed to that value or parameter per se. For example, the description that refers to about X includes the description of X. Numeric ranges include the numbers that define the range.

[0179] It is understood that wherever modalities are described in this document with the language comprising, modal Petition 870260028237, dated 03 / 25 / 2026, p. 873 / 1082 53 / 230 similar properties described in terms of consisting of and / or consisting essentially of are also provided.

[0180] Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group lacking one or more members of the group. The invention also provides for the explicit exclusion of one or more of any of the members in the claimed invention.

[0181] Unless defined otherwise, all technical and scientific terms used in this document have the same meaning as commonly understood by those skilled in the art to which this description pertains. In case of conflict, this descriptive report, including definitions, shall prevail. Throughout this descriptive report and claims, the word "comprises" or variations such as "comprises" or "comprising" shall be understood as implying the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers. Unless otherwise required by the context, singular terms shall include plurals and plural terms shall include the singular.

[0182] Exemplary methods and materials are described in this document, although methods and materials similar or equivalent to those described in this document may also be used in the practice or testing of the invention. The materials, methods and examples are illustrative only and are not intended to be limiting. Specific cars for CD70 and their manufacturing methods.

[0183] The present description provides CARs that bind to CD70 (e.g., human CD70 (e.g., SEQ ID NO: 335), according Petition 870260028237, dated 03 / 25 / 2026, p. 874 / 1082 54 / 230 me those deposited in accordance with the provisions of the Budapest Treaty and designated accession number: P32970-1. The CD70-specific CARs provided in this document include single-chain CARS and multi-chain CARS. In some embodiments, CARS have the ability to redirect the specificity and reactivity of T cells to CD70 in a non-MHC-restricted manner, exploiting the antigen-binding properties of monoclonal antibodies. Non-MHC-restricted antigen recognition confers on T cells expressing CARS the ability to recognize an antigen independent of antigen processing, thus bypassing a key tumor escape mechanism.

[0184] In some embodiments, the CARs provided in this document comprise an extracellular ligand-binding domain (e.g., a single-chain variable fragment (scFv)), a transmembrane domain, and an intracellular signaling domain. In some embodiments, the CARs provided in this document further comprise a hinge or stalk domain, which may be situated between the extracellular ligand-binding domain and the transmembrane domain. In some embodiments, the extracellular ligand-binding domains, the transmembrane domain, and the intracellular signaling domain are in a single polypeptide, i.e., in a single chain. Multi-chain CARs and polypeptides are also provided in this document.In some embodiments, multichain CARs comprise: a first polypeptide comprising a transmembrane domain and at least one extracellular ligand-binding domain and a second polypeptide comprising a transmembrane domain and at least one intracellular signaling domain, wherein the polypeptides join to form a multichain CAR. In some embodiments, CARs are inducible, such as by small molecules (e.g., AP1903) or proteins (e.g., Petition 870260028237, dated 03 / 25 / 2026, pp. 875 / 1082 55 / 230 plo, Epo, Tpo, or PD-1). In some embodiments, a CD70-specific multi-chain CAR is based on the high-affinity IgE receptor (FcεRI). FcεRI expressed on mast cells and basophils triggers allergic reactions. FcεRI is a tetrameric complex composed of a single α subunit, a single β subunit, and two disulfide-linked γ subunits. The α subunit contains the IgE-binding domain. The β and γ subunits contain ITAMs that mediate signal transduction. In some embodiments, the extracellular domain of the FcRα chain is deleted and replaced by a CD70-specific extracellular ligand-binding domain. In some embodiments, the CD70-specific multi-chain CAR comprises a scFv that specifically binds to CD70, the CD8α hinge, and the FcRβ chain ITAM. In some modalities, the CAR may or may not include the FcRy chain.

[0185] In some embodiments, the extracellular ligand-binding domain comprises a scFv comprising the variable light chain (VL) region and the variable heavy chain (VH) region of a target antigen-specific monoclonal antibody (i.e., CD70) linked by a flexible peptide linker. Single-chain variable region fragments are made by linking variable light and / or heavy chain regions using a short linker peptide (Bird et al., Science 242:423-426, 1988). An example of a linker peptide is the GS peptide linker with the amino acid sequence (GGGGS)3 (SEQ ID NO: 296), which links approximately 3.5 nm between the carboxy terminus of one variable region and the amino terminus of the other variable region. Peptide linkers of other sequences have been designed and used (Bird et al., 1988, supra).Other exemplary peptide linkers may generally include other GS peptide linkers may generally include (GGGGS)x, where x is 1, 2, 3, 4, 5 (SEQ ID NO: 613). In some embodiments, x is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or. Petition 870260028237, dated 03 / 25 / 2026, page 876 / 1082 56 / 230 any integer less than about 20. In some embodiments, the peptide linker is (GGGGS)4 (SEQ ID NO: 602). In some embodiments, the peptide linker is GSTSGSGKPGSGEGSTKG (SEQ ID NO: 612), as described in Whitlow et al, Protein Eng. (1993) 6(8): 989-895. In general, peptide linkers can be short, flexible polypeptides that, in some embodiments, are composed of about 20 or fewer amino acid residues. Peptide linkers can, in turn, be modified for additional functions such as drug binding or binding to solid supports. Single-chain variants can be produced recombinantly or synthetically. For the synthetic production of scFv, an automated synthesizer can be used.For recombinant production of scFv, a polynucleotide containing a suitable plasmid encoding scFv can be introduced into a suitable host cell, either eukaryotic, such as yeast, plant, insect, or mammalian cells, or prokaryotic, such as E. coli. The polynucleotides encoding scFv of interest can be made by routine manipulations, such as polynucleotide linkage. The resulting scFv can be isolated using standard protein purification techniques known in the art.

[0186] In another aspect, a CAR is provided, which specifically binds to CD70, wherein the CAR comprises an extracellular ligand-binding domain comprising: a VH region comprising a VH CDR1, VH CDR2 and VH CDR3 of the VH sequence indicated in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46 or 48; and / or a VL region comprising VL CDR1, VL CDR2, and VL CDR3 of the VL sequence indicated in 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, or 47. In some embodiments, VH and VL are linked by a flexible peptide linker. In some embodiments, a flexible peptide linker comprises the amino acid sequence indicated in SEQ ID NO: 296. Petition 870260028237, dated 03 / 25 / 2026, page 877 / 1082 57 / 230

[0187] In some embodiments, a CAR of the description comprises an extracellular ligand-binding domain with any one of the partial light chain sequences as listed in Table 1 and / or any one of the partial heavy chain sequences as listed in Table 1. In Table 1, underlined sequences are CDR sequences according to Kabat and bold sequences according to Chothia. Table 1 mAb Light Chain Heavy Chain 31H1 DIVMTQNPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQSPRLLIYKISNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCMQATQFPL- QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYGFSWVRQAPGQGLEWMGGIIPIFGSANYAQKFQGRVTITADKSTSTVYM ELISL RSEDTAVYYCARGGSSSPFAYWGQG- TIGGGSKVEIK (SEQ ID NO:1).TLVTVSS (SEQ ID NO: 2) 63B2 DIVMTQTPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQSPRLLIYKISNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCMQATQFPLTIGGGSKVEIK (SEQ ID NO: 3 ) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYGFSWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTVFMELISLRSEYTAVYYCARGGSSSPFAYWGQGTLVTVSS (SEQ ID NO: 4) 40E3 DIQMTQSPSSLSAS- VGDRVTITCRASQGISNYLAWFQQKPGKAPKSLI- YAASSLQSGVPSK- FSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK (SEQ ID NO: 5) QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWNWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLRSVTAADTAVYYCARDIRTWGQGTLVTVSS (SEQ ID NO: 6) 42C3 DVVMTQSPLSLPVTLGQPASISC RSSQSLVYSDENTYLNWFQQRPGQSLRRLIYQVSNRDSGVPDRFSGSGSGTDFTLKISRVEAE DVGVYFCMQGTYWPPTFGGGTKVEIK (SEQ ID NO: 7) EVQLVESGGGLVQPGGSLRLSCAASGFTFRNSWMSWVRQAPGKGLEWVANIKRDGSEKYYVDSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDQTGSFDYWGQGTLVTVSS (SEQ ID NO: 8). Petição 870260028237, de 25 / 03 / 2026, pág. 878 / 1082 58 / 230 mAb Cadeia Leve Cadeia Pesada 45F11 EIVMTQSPATLSMSLGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYGASTRATGIPARFGGSGSGTEFTLTISSLQSEDFAVYYCQQYINWPHFGGGTKVEIK (SEQ ID NO: 9) QVQLRGSGPGLVKPSETLSLTCTVS DDSISVYYWS WIRQPAGKGLEWIGRVYSSGNINYNPSLESRVTMSVDTSKSRFSLNLSSVTAADTAVYYCARGLDAFDIWGQGTMVTVSS (SEQ ID NO: 10) 64F9 DIQMTQSPSSLSAS- VGDRVTITCQASQDIS- NYLNWYQQKPGKAPKILIYGASNLETGVPS- RFSGSGSGTDFTFAISSLQPE DVATYYCQQYDNFPITFGQGTRLEIK (SEQ ID NO: 11) EVQLLESGGGLVQPGESLRLSCEVSGFTFTSYAMSWVRQVPGKGLEWVSIISGVAFTTYYADSVKGRFTISRDHSKNTLYLQMNGLRAEDTAVYYCVKVDGEVYWGQGTLVTVSS (SEQ ID NO: 12) 72C2 EIVMTQSPDTLSVSPGERAILSCRASQSVSSNLAWYQQKPGQAPRLLIYSASTRASGIPARFSGSGSGTEFTLSISSLQSEDFAVYYCQQYDNWPPLTFGGGTKVEIK (SEQ ID NO: 13) QVQLVQSGAEVKKPGSSVKVSCEASGGTFITYAISWVRQAPGQGLEWMGGIIPFFGTANYAQKFQGRVTITADKSTSTASMELRSLRSEDTAMYYCAQWELFFFDFWGQGTPVTVSS (SEQ ID NO: 14) 2F10 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQQPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAIYYCQQYGSSPLTFGGGTKVEIK (SEQ ID NO: 15)AVQLVESGGGLVQPGGSLRLSCAASGFTFTYYSMNWVRQAPGKGLEWVSHISIRSSTIYFADSAKG RFTISRDNAKNSLYLQMNSLRDEDTAVYCARGSGWYGDYFDYWGQGTLVTVSS (SEQ ID NO: 16) 4F11 DIQMTQSPSAMSASVGDRVTITCRASQDISNYLAWFQQKPGKVPRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEIN (SEQ ID NO: 17) QVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKS RLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWGQGTLVSVSS (SEQ ID NO: 18) Petition 870260028237, de 25 / 03 / 2026, pág. 879 / 1082 59 / 230 mAb Cadeia Leve Cadeia Pesada 10H10 DIQMTQSPSSVSASVGDRVTITC RASQGISSWLAWYQQKPGKAPKVLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAFSFPFTFGPGTKVDIK (SEQ ID NO: 19) EVQLVESGGGLVQPGGSLRLSCAVSGFTFSNHNIHWVRQAPGKGLEWISYISRSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARDHAQWYGMDVWGQGTTVTVSS (SEQ ID NO: 20) 17G6 DIVMTQSPDSLAVSLGERATINC KSSQSVLYSYNN KN KVEIK (SEQ ID NO: 21) SEQ ID NO: 21 EVQVVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSHSSISRGNIYFADSVKG RFTISRDNAKNSLYLQMNSLRDEDTAVYYCARGSGWYGDYFDYWGQGTLVTVSS (SEQ ID NO: 24) P02B10 ELQSVLTQPPSASG- TPGQRVTISCSGSSS- NIGSNYVYWYQQLPGTA- EVQLLESGGGLVQPGGSLRLSCAASGFAFSNYAMSWVRQAPGKGLEWVSAIRGGGGSTYYPKLLIYRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDDSLSGVVFGGGTKLTVL (SEQ ID NO: 25) ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDFISGTWYPDYWGQGTLVTVSS (SEQ ID NO: 26) P07D03 ELQSVLTQPPSASGTPGQRVTISCSGSRSNIGSNYVYWYQQLPGTAPKLLIYRNNQRPSGVP- EVQLVQSGAEVKKPGESLKISCKGSGYRFTSYWIGWVRQMPGKGLEWMGSIYPDDSDTRYSPSFQGQVTISADKSIS- DRFSGSKSGTSASLAISGLRSEDEADYYC ASWDGSLSAVVFGTGTKLTVL (SEQ ID NO: 27) TAYLQWSSLKASDTAMYYCASSTVDYPGYSYFDYWGQGTLVTVSS ((SEQ ID NO: 28) Petição 870260028237, de 25 / 03 / 2026, pág. 880 / 1082 60 / 230 mAb Cadeia Leve Cadeia Pesada P08A02 ELQSVLTQPPSASG- TPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYRNNQRPSGVP- EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYWIAWVRQMPGKGLEWMGIIYPDGSDTRYSPSFQGQVTISADKSIS- DRFSGSKSGTSASLAISGLRSEDEADYYC ATWDDSLGSPVFGTGTKLTVL (SEQ ID NO: 29) TAYLQWSSLKASDTAMYYCARDITSWYYGEPAFDIWGQGTLVTVSS ((SEQ ID NO: 30) P08E02 ELDIQMTQSPSSLSAS- VGDRVTITCRASQSIS- RYLNWYQQKPGKAPKLLIYAASILQTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTTMW EVQLVQSGAEVKKPGESLKISCKGSGYSFTSSWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCAKGLSQAMTGFG- TFGQGTKVEIK (SEQ ID NO: 31) FDYWGQGTLVTVSS (SEQ ID NO: 32) P08F08 ELQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYGDYQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATRDDS- EVQLVQSGAEVKKPGESLKISCKGSGYGFTSYWIGWVRQMPGKGLEWMGIIHPDDSDTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSYLRGLWGGYFDYWGQGTLVTVSS LSGSVVFGTGTKLTVL (SEQ ID NO: 33) ((SEQ ID NO: 34) P08G02 ELDIQMTQSPSSLSASVGDRVTITCRASQSIYDYLHWYQQKPGKAPKLLIYDASNLQSGV-EVQLVQSGAEVKKPGESLKIISCKGSGYTFPSSWIGWVRQMPGKGLEWMGIIYPDTSHTRYSPSFQGQVTISADK- PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPLFT SISTAYLQWSSLKAS- DTAMYYCARASYFDRG- FGQGTKVEIK (SEQ ID NO: 35) TGYSSWWM DVWGQGTLVTVSS ((SEQ ID NO: 36) P12B09 ELDIQMTQSPSSLSASVGDRVTITCRASQYIGRYLNWYQQKRGKAPKLLIHGATSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTTSPT FGQGTKVEIK (SEQ ID NO: 37) EVQLLESGGGLVQPGGSLRLSCAASGFTFSQYSMSWVRQAPGKGLEWVSAISGGGVSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASDISDSGGSHWYFDYWGQGTLVTVSS (SEQ ID NO: 38) Petition 870260028237, on 03 / 25 / 2026, page. 881 / 1082 61 / 230 mAb Cadeia Leve Cadeia Pesada P12F02 ELQSVLTQPPSASGTPGQRVTISCSGSTSNIGRNYVYWYQQLPGTAPKLLIYRTNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDDSLSGRVFGTGTKLTVL (SEQ ID NO: 39) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTISGTGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVRAGIDPTASDVWGQGTLVTVSS (SEQ ID NO: 40) P12G07 ELQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKPLIYMNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDDSLSAVVFGTGTKLTVL ((SEQ ID NO: 41) EVQLLESGGGLVQPGGSLRLSCAASGFTFNNFAMSWVRQAPGKGLEWVSGISGSGDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRDIGLGWYSYYLDVWGQGTLVTVSS (SEQ ID NO: 42) P13F04 ELQSVLTQPPSASGTPGQRVTISCSGSNSNIGTNYVSWYQQLPGTAPKLLIYRSSRRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDGSLSGHWVFGTGTKLTVL (SEQ ID NO: 43) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGEIIPIFGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARAGWDDSWFDYWGQGTLVTVSS (SEQ ID NO: 44) P15D02 ELDIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYSASSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYST-P16C05 SEQ ID NO: 47 EVQLVQSGAEVKKPGESLKIISCKGSGYSFTDYWIGWVRQMPGKGLEWMGMISPGGSTTIYRPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCAREMYTGGYGGSWYFDYWGQG TLVTVSS(SEQ ID NO: 48) Petition 870260028237, on 03 / 25 / 2026, page. 882 / 1082 62 / 230 mAb Cadeia Leve Cadeia Pesada 10A1 DIQMTQSPSTLSASVGDRVTITC RASQSISTWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTEFILTINSLQPDD FASYYCQQYKSYSHTFGQGTKLEIK (SEQ ID NO: 338) QVQLQESGPGLVKPSETLSLTCTVSGGSISYYYWTWIRQPPGKGLEWIGHIYYSGSTNYNPSLKSRVTISIDTSKNLFSLKLSSVTAADTAVYYCARAEGSlDAFDFWGQGTMVTVSS (SEQ ID NO: 339) 10E2 DIQMTQSPSTLSAS- VGDRVTITCRASQSISSWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTEFTLTINSLQPDD FATYYCQQYKSFSLTFGQGTKLEIK (SEQ ID NO: 340) EVQLVESGGGLIQPGGSLRLSCAASGFTVSSNYMTWVRQAPGKGLEWVSVIYSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNWGDYWGQGTLVTVSS (SEQ ID NO: 341) 11A1 DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKVLIYKASTLESGVPSRFSGSGSGTEFTLTISSLQPDD FATYYCQQYNSYSYTFGHGTKLEIK (SEQ ID NO: 342) QVQLQESGPGLVKPSGTLSLTCTVSGGSIDYYFWNWFRQSPVKGLEWIGHVYDIGNTKYNPSLKSRVTISIDTSENQFSLKLNSVTAADTAVYYCARGEGAlDAFDIWGQGTMVTVSS (SEQ ID NO: 343) 11C1 DIQMTQSPSILSASVGDRVTITCRASQSVSSWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGTGSGTEFTLTISSLQSDDFATYYCQQYNTYSHT-11D1 AIQMTQSPSSLSAS- VGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISS- LQPEDFATYYC LQDYNYPFTFGPGTKVDIK (SEQ ID NO: 346) QVQLVESGGGVVQPGRSLRLSCVASGFTFSDYGIHWVRQAPGMGQEWVAVIWYDGSiKKYSDSVKG RFIISRDNSENTVYLQMNSLRGEDTAIYYCARDEVGtfGAFDFWGQGTKVTVSS (SEQ ID NO: 347) Petition 870260028237, on 03 / 25 / 2026, page. 883 / 1082 63 / 230 mAb Cadeia Leve Cadeia Pesada 11E1 DIQMTQSPSSLSASVGDSITITCRASQDIDNYLAWYQQKTGKVPKVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPE DVATYYCQNYNSGPRTFGQGTKVEIK (SEQ ID NO: 348) 12A2 DIQMTQSPSSLSSASVGDRVTITCRASQDISNYLTWYQQKPGRFPEVLIYAASALQSGVPSRFSGSGSGTDFTLTISSLQPE DVATYYCQNYNSAPRTFGQGTKVEIK (SEQ ID NO: 350) 12C4 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQVLILLGSNRASGVPDRVSASGSGTDFTLKISRMQAEDVGIYYCMQTLQTPFTFGQGTKLEIK (SEQ ID NO: 352) 12C5 DIQLTQSPSFLSASVGDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLDIN (SEQ ID NO:354)EVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSS (SEQ ID NO: 355) 12C6 DIQLTQSPSFLSASVGDRVIITCRASQGINSHLAWYQQKPGKAPKLLIYYASTLPSGVPSRFSGSGSGTEFTLTVTSLQPEDFATYYCQQLNHYPITFGQGTRLEIK (SEQ ID NO: 661) EVELVESGGGMVQPGRSLRLSCAASGFTFSDYGMHWVRQAPGMGLEWVTVIWYDGSnKYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDTAVYYCARDEVGfvGAFDIWGQGTMVTVSS (SEQ ID NO: 662) Petição 870260028237, de 25 / 03 / 2026, pág. 884 / 1082 64 / 230 mAb Cadeia Leve Cadeia Pesada 12D3 DIQMTQSPSSLSASVGDRVTITC RASQGISNYLAWYQQKPGKVPKLLIYAASTLHSGVPSRFSGSGSGTDFTLTISSLQPE DVATYYCQKYNSAPRTFGQGTKVEIK (SEQ ID NO: 356) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSdgYYWSWIRQHPGKGLEWIG YMYYSGITYHNPSLKSRVTISVDTSKNQFSLRLSSVTAADTAVYYCARDFGWYFDLWGRGTLVTVSS (SEQ ID NO: 357) 12D6 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKVPKLLIYAASTLHSGVPSRFSGSGSGTDFTLTISSLQPDD FAAYYCQKYNSAPRTFGQGTKVEIK (SEQ ID NO: 358) QVQLQESGPGLVKPSQTLSLTCTVSGGSISSdaYYWSWIRQHPGKGLEWIGYMYYSGITYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDFGWYFDLWGRGTLVTVSS (SEQ ID NO: 359) 12D7 DIQLTQSPSFLSASVGDRVSITCRASQDISSFLAWYQQKPGKAPVLLIYVASTLQSGVPSRFSGSGSGTEFTLTVSSLQPEDFATYYCQQLHVYPITFGQGTRLEIR (SEQ ID NO: 360) QVQLVESGGGVVQPGRSLRLSCVASGFTFSDYGIHWVRQAPGMGQEWVAVIWYDGSiKKYSDSVKGRFIISRDNSENTVYLQMNSLRGEDTAIYYCARDEVGtfGAFDFWGQGTKVTVSS (SEQ ID NO: 361) 12F5 DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDDGNtYLDWYLQKPGQSPQLLIYTLSYRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEFPFTFGPGTKVDIK (SEQ ID NO: 362)EVQLVESGGGLVKPGGSLRLSCAASGFFTFSNAWMSWVRQAPGKGLEWVGRIKsktGGGTTDYAAPVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCTSLIVGaiSLFDYWGQGTLVTVSS (SEQ ID NO: 363) 12H4 DIQMTQSPSALSASVGDRVAITCRASQTISTWLAWYQQKPGKAPKVLIYKASNLESGVPSRFSGSGSGTEFTLTINSLQPDD FATYYCQQYQTFSHT- QVQLRESGPGLVKPSETLSLTCTISGGSISYYFWTWIRQPPGRGLEWIGQIYYSGNTNSNPSLKSRVTISIDTSKNQFSLKLTSVTVADTAVYYCVRAEGSlDAFDIWGQG- FGQGTKLEIK (SEQ ID) NO: 364) TMVAVSS (SEQ ID NO: 365) Petition 870260028237, on 03 / 25 / 2026, page. 885 / 1082 65 / 230 mAb Cadeia Leve Cadeia Pesada 8C8 DMQMTQSPSSLSASVGDRVTLTC RASQGISNYLAWFQLKPGKVPKLLI- YAASTLQSGVPS- RFSGSGSGTDFALTISSLQPEDVATYYCQKYNSAPLT- EVQLVESGGGLVKPGGSLRLSCVASGFTFSSYSMNWVRQFPGKGLEWVSSIStSSNYIHYADSLQGRFTISRDNAKNSLYLQMSSLRVEDTAVYYCVRDKGTtltnWYFDLWGRGTLVTVSS FGGGTKVEIK (SEQ ID NO: 366) (SEQ ID NO: 367) 8F7 DIVMTQSPLSLPVTPGEPASISCRSSQTLVHSNGYNYLNWYL QKPGQSPQLLIYLGSNRASGVPDRFSGSGSGSDFTLKISRMEAE DVGVYYC MQAIQTPYTFGQGTNVEIK (SEQ ID NO: 368) 8F8 DIQMTQSPSTLSSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKVLIYKASNLESGVPSRFSGSGSGTEFTLTISSLQPDD FATYYCQQYNSYSCTFGQGTKLEIK (SEQ ID NO: 370) 9D8 DIQMTQSPSSLSASVGDRIIFTCQASQDINNYLHWYQQKPGKAPKLLIYDASDWETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYDHLPITFGQGTRVEIK (SEQ ID NO: 372)QVQLVQSGAEVTKPGASVKVSCKASGYIFTGYYIYWVRQAPGQGLEWMGWINpSSGGTNYAQKFQG RVTMARDTSISTAYMELSSLRSDDTAVYYCARDRKReyyynFGMDVWGQGTTVTVST (SEQ ID NO: 373) 9E10 DIQMTQSPSSLSSASVGDR- VILTCQASQDISNYLHWYQQKPGKAPKLLIYDASDLETGVPSRFSGSGSGADFTFTISNLQPEDFATYYCQQYDHLPITFGQGTRLEIK (SEQ ID NO: 374) QVQLVQSGAEVTKPGASVKVSCKASGYTFTSHYIYWVRQAPGQGLEWMGWINpNSGGTNYAQKFQD RVTMARDTSISTAYMELSRLRSDDTAVYYCAKDRKReyyynFGMDVWGQGTTVTVSA (SEQ ID NO: 375) Petition 870260028237, on 03 / 25 / 2026, page. 886 / 1082 66 / 230 mAb Cadeia Leve Cadeia Pesada 9E5 DIQMTQSPSSLSASVGDRVILTCQASQDISNYLHWYQQKPGKAPKLLIYDASDLETGVPSRFSGSGSGADFTFTISNLQPEDFATYYCQQYDHLPITFGQGTRLEIK (SEQ ID NO: 376) QVQLVQFGVEVRKPGASVKVSCKVSGFTFTSHYIYWVRQAPGQGLEWMGWINpNSGGTKYAQKFQDRVTMARDTSISTAYMELSRLRSDDTSVYYCVKDRKReyyynFGMDVWGQGTTVTVSS (SEQ ID NO: 377) 9F4 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLPYTFGQGTKLEIK (SEQ ID NO: 378) EVQMLESGGGLIQPGGSLRLSCKTSGFTLSIYAIHWVRQAPGRGLEWVSSFGgRGSSTYFADSVKG RFTISRDASENSLYLHMNSLRAEDTAVYYCAKEKDWgRGFDYWGQGTLVTVSS (SEQ ID NO: 379) 9F8 DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNYLDWYLQKPGQSPQLLIFLNSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCMQALQTPLTFGGGTKVEIK (SEQ ID NO: 380) EVQLVESGGGLVKPGGSLRLSCAASGFTFSNYSMNWVRQAPGKGLEWVSSISsSTIYIYYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTAVYYCARDl· GWevftLGFDYWGQGTQVTVSS (SEQ ID NO: 381)

[0188] This document also provides portions of CDRs from extracellular ligand-binding domains of CARs to CD70 (including Chothia CDRs, Kabat CDRs, and CDR contact regions). The determination of CDR regions is within the art. It is understood that in some embodiments, CDRs may be a combination of Kabat and Chothia CDRs (also referred to as combined CRs or extended CDRs). In some embodiments, the CDRs are Kabat CDRs. In other embodiments, the CDRs are Chothia CDRs. In other words, in embodiments with more than one CDR, the CDRs may be Kabat, Chothia, combination CDRs, or combinations thereof. Tables 2A-2B provide examples of CDR sequences provided in this document. Petition 870260028237, dated 03 / 25 / 2026, pages 887 / 1082 67 / 230 Table 2A Cadeia Pesada mAb CDRH1 CDRH2 CDRH3 31H1 SYGFS (SEQ ID NO: 49) (Kabat); GGTFSSY (SEQ ID NO: 50) (Chothia); GGTFSSYGFS (SEQ ID NO: 51) (Estendida) GIIPIFGSANYAQKFQG (SEQ ID NO: 52) (Kabat); IPIFGS(SEQ ID NO: 53) (Chothia) GGSSSPFAY(SEQ ID NO: 54) 63B2 SYGFS(SEQ ID NO: 55) (Kabat); GGTFSSY (SEQ ID NO: 56) (Chothia) GGTFSSYGFS (Estendida) (SEQ ID NO: 57) GIIPIFGTANYAQKFQG (SEQ ID NO: 58) (Kabat); IPIFGT (SEQ ID NO: 59) (Chothia) GGSSSPFAY(SEQ ID NO: 60) 40E3 SYYWN (SEQ ID NO: 61) (Kabat); GGSISSY (SEQ ID NO: 62) (Chothia); GGSISSYYWN (SEQ ID NO: 63) (Estendida) YIYYSGSTNYNPSL KS (SEQ ID NO: 64) (Kabat); YYSGS (SEQ ID NO: 65) (Chothia) DIRTW (SEQ ID NO: 66) 42C3 NSWMS (SEQ ID NO: 67) (Kabat); GFTFRNS (SEQ ID NO: 68) (Chothia); GFTFRNSWMS (SEQ ID NO: 69) (Estendida) NIKRDGSEKYYVDSVKG (SEQ ID NO: 70) (Kabat); KRDGSE (SEQ ID NO: 71) (Chothia) DQTGSFDY(SEQ ID NO: 72) 45F11 VYYWS (SEQ ID NO: 73) (Kabat); DDSISVY (SEQ ID NO: 74) (Chothia);DDSISVYYWS (SEQ ID NO: 75) (Extended) VYSSGNINYNPSLE S (SEQ ID NO: 76) (Kabat); YSSGN (SEQ ID NO: 77) (Chothia) GLDAFDI (SEQ ID NO: 78) 64F9 SYAMS (SEQ ID NO: 79) (Kabat); GFTFTSY (SEQ ID NO: 80) (Chothia); GFTFTSYAMS (SEQ ID NO: 81) (Extended) RVYSSGNINYNPSL ES (SEQ ID NO: 82) (Kabat); YSSGN (SEQ ID NO: 83) (Chothia) GLDAFDI (SEQ ID NO: 84); Petition 870260028237, dated 03 / 25 / 2026, pages 888 / 1082 68 / 230 Cadeia Pesada mAb CDRH1 CDRH2 CDRH3 72C2 TYAIS (SEQ ID NO: 85) (Kabat); GGTFITY (SEQ ID NO: 86) (Chothia); GGTFITYAIS (SEQ ID NO: 87) (Estendida) GIIPFFGTANYAQKFQG (SEQ ID NO: 88) (Kabat); IPFFGT (SEQ ID NO: 89) (Chothia) WELFFFDF (SEQ ID NO: 90) 2F10 YYSMN (SEQ ID NO: 91) (Kabat); GFTFTYY (SEQ ID NO: 92) (Chothia); GFTFTYYSMN (SEQ ID NO: 93) (Estendida) HISIRSSTIYFADSA KG (SEQ ID NO: 94) (Kabat); SIRSST (SEQ ID NO: 95) (Chothia) GSGWYGDYFDY (SEQ ID NO: 96) 4F11 NARMGVT (SEQ ID NO: 97) (Kabat); GFSLSNARM (SEQ ID NO: 98) (Chothia); GFSLSNARMGVT (SEQ ID NO: 99) (Estendida) HIFSNDEKSYSTSL KS (SEQ ID NO: 100) (Kabat); FSNDE (SEQ ID NO: 101) (Chothia) IRDYYDISSYYDY (SEQ ID NO: 102) 10H10 NHNIH (SEQ ID NO: 103) (Kabat); GFTFSNH (SEQ ID NO: 104) (Chothia); GFTFSNHNIH (SEQ ID NO: 105) (Estendida) YISRSSSTIYYADSVKG (SEQ ID NO: 106) (Kabat); SRSSST (SEQ ID NO: 107) (Chothia) DHAQWYGMDV (SEQ ID NO: 108) 17G6 SYWMS (SEQ ID NO: 109) (Kabat); GFTFSSY (SEQ ID NO: 110) (Chothia);GFTFSSYWMS (SEQ ID NO: 111) (Estendida) SIKQDGSEKYYVDS VKG (SEQ ID NO: 112) (Kabat); KQDGSE (SEQ ID NO: 113) (Chothia) EGVNWGWRLYWHFDL (SEQ ID NO: 114) 65E11 SYSMN (SEQ ID NO: 115) (Kabat); GFTFSSY (SEQ ID NO: 116) (Chothia); GFTFSSYSMN (SEQ ID NO: 117) (Estendida) HSSISRGNIYFADS VKG (SEQ ID NO: 118) (Kabat); SISRGN (SEQ ID NO: 119) (Chothia) GSGWYGDYFDY (SEQ ID NO: 120); Petition 870260028237, on 03 / 25 / 2026, page. 889 / 1082 69 / 230 Cad eia Pesada mAb CDRH1 CDRH2 CDRH3 P02B10 NYAMS (SEQ ID NO: 121) (Kabat); GFAFSNY (SEQ ID NO: 122) (Chothia); GFAFSNYAMS (SEQ ID NO: 123) (Estendida) AIRGGGGSTYYAD SVKG (SEQ ID NO: 124) (Kabat); RGGGGS (SEQ ID NO: 125) (Chothia) DFISGTWYPDY (SEQ ID NO: 126) P07D03 SYWIG (SEQ ID NO: 127) (Kabat); GYRFTSY (SEQ ID NO: 128) (Chothia); GYRFTSYWIG (SEQ ID NO: 129) (Estendida) SIYPDDSDTRYSPS FQG (SEQ ID NO: 130) (Kabat); YPDDSD (SEQ ID NO: 131) (Chothia) STVDYPGYSYFDY (SEQ ID NO: 132) P08A02 NYWIA (SEQ ID NO: 133) (Kabat); GYTFTNY (SEQ ID NO: 134) (Chothia); GYTFTNYWIA (SEQ ID NO: 135) (Estendida) IIYPDGSDTRYSPSF QG (SEQ ID NO: 136) (Kabat); YPDGSD (SEQ ID NO: 137) (Chothia) DITSWYYGEPAFDI (SEQ ID NO: 138) P08E02 SSWIG (SEQ ID NO: 139) (Kabat); GYSFTSS (SEQ ID NO: 140) (Chothia); GYSFTSSWIG (SEQ ID NO: 141) (Estendida) IIYPGDSDTRYSPSF QG (SEQ ID NO: 142) (Kabat); YPGDSD (SEQ ID NO: 143) (Chothia) GLSQAMTGFGFDY (SEQ ID NO: 144) P08F08 SYWIG (SEQ ID NO: 145) (Kabat);GYGFTSY (SEQ ID NO: 146) (Chothia); GYGFTSYWIG (SEQ ID NO: 147) (Estendida) IIHPDDSDTKYSPSF QG (SEQ ID NO: 148) (Kabat); HPDDSD (SEQ ID NO: 149) (Chothia) SYLRGLWGGYFDY (SEQ ID NO: 150) P08G02 SSWIG (SEQ ID NO: 151) (Kabat); GYTFPSS(SEQ ID NO: 152) (Chothia); GYTFPSSWIG (SEQ ID NO: 153) (Estendida) IIYPDTSHTRYSPSF Q (SEQ ID NO: 154) (Kabat); YPDTSH (SEQ ID NO: 155) (Chothia) ASYFDRGTGYSSWWMDV (SEQ ID NO: 156); Petition 870260028237, on 03 / 25 / 2026, page. 890 / 1082 70 / 230 Cad eia Nest mAb CDRH1 CDRH2 CDRH3 P12B09 QYSMS (SEQ ID NO: 157) (Kabat); GFTFSQY (SEQ ID NO: 158) (Chothia); GFTFSQYSMS (SEQ ID NO: 159) (Extended) AISGGGVSTYYADSVK G (SEQ ID NO: 160) (Kabat); SGGGVS (SEQ ID NO: 161) (Chothia) DISDSGGSHWYFDY (SEQ ID NO: 162) P12F02 SYAMS (SEQ ID NO: 163) (Kabat); GFTFSSY (SEQ ID NO: 164) (Chothia); GFTFSSYAMS (SEQ ID NO: 165) (Extended) TISGTGGTTTYYADS VKG (SEQ ID NO: 166) (Kabat); SGTGGT (SEQ ID NO: 167) (Chothia) VRAGIDPTASDV (SEQ ID NO: 168) P12G07 NFAMS (SEQ ID NO: 169) (Kabat); GFTFNNF (SEQ ID NO: 170) (Chothia); GFTFNNFAMS (SEQ ID NO: 171) (Extended) GISGSGDNTYYADS VKG (SEQ ID NO: 172) (Kabat); SGSGDN (SEQ ID NO: 173) (Chothia) DRDIGLGWYSYYLDV (SEQ ID NO: 174) P13F04 SYAIS (SEQ ID NO: 175) (Kabat); GGTFSSY (SEQ ID NO: 176) (Chothia); GGTFSSYAIS (SEQ ID NO: 177) (Extended) EIIPIFGTASYAQKFQG (SEQ ID NO: 178) (Kabat); IPIFGT (SEQ ID NO: 179) (Chothia) AGWDDSWFDY (SEQ ID NO: 180) P15D02 SYWIG (SEQ ID NO: 181) (Kabat);GYSFASY (SEQ ID NO: 182) (Chothia); GYSFASYWIG (SEQ ID NO: 183) (Estendida) VIYPGTSETRYSPS FQG (SEQ ID NO: 184) (Kabat); YPGTSE (SEQ ID NO: 185) (Chothia) GLSASASGYSFQY (SEQ ID NO: 186) P16C05 DYWIG (SEQ ID NO: 187) (Kabat); GYSFTDY (SEQ ID NO: 188) (Chothia); GYSFTDYWIG (SEQ ID NO: 189) (Estendida) MISPGGSTTIYRPS FQG (SEQ ID NO: 190) (Kabat); SPGGST (SEQ ID NO: 191) (Chothia) MYTGGYGGSWYF DY (SEQ ID NO: 192); Petition 870260028237, on 03 / 25 / 2026, page. 891 / 1082 71 / 230 Cadeia Pesada mAb CDRH1 CDRH2 CDRH3 10A1 YYYWT (SEQ ID NO: 382) (Kabat); GGSISYY (SEQ ID NO: 383) (Chothia); GGSISYYYWT (SEQ ID NO: 384) (Estendida) HIYYSGSTNYNPSL KS (SEQ ID NO: 385) (Kabat); YYSGS (SEQ ID NO: 386) (Chothia) AEGSlDAFDF (SEQ ID NO: 387) 10E2 SNYMT (SEQ ID NO: 388) (Kabat); GFTVSSN (SEQ ID NO: 389) (Chothia); GFTVSSNYMT (SEQ ID NO: 390) (Estendida) VIYSGGSTYYADSV KG (SEQ ID NO: 391) (Kabat); YSGGS (SEQ ID NO: 392) (Chothia) NWGDYW (SEQ ID NO: 393) 11A1 YYFWN (SEQ ID NO: 394) (Kabat); GGSIDYY (SEQ ID NO: 395) (Chothia); GGSIDYYFWN (SEQ ID NO: 396) (Estendida) HVYDIGNTKYNPSL KS (SEQ ID NO: 397) (Kabat); YDIGN (SEQ ID NO: 398) (Chothia) GEGAlDAFDI (SEQ ID NO: 399) 11C1 YYYWT (SEQ ID NO: 400) (Kabat); GGSISYY (SEQ ID NO: 401) (Chothia); GGSISYYYWT (SEQ ID NO: 402) (Estendida) HVIYSGTTNYNPSL KS (SEQ ID NO: 403) (Kabat); IYSGT (SEQ ID NO: 404) (Chothia) AEGSlDAFDL (SEQ ID NO: 405) 11D1 DYGIH (SEQ ID NO: 406) (Kabat); GFTFSDY (SEQ ID NO: 407) (Chothia);GFTFSDYGIH (SEQ ID NO: 408) (Estendida) VIWYDGSiKKYSDSVKG (SEQ ID NO: 409) (Kabat); WYDGSi (SEQ ID NO: 410) (Chothia) DEVGtfGAFDF (SEQ ID NO: 411) 11E1 SdgYYWS (SEQ ID NO: 412) (Kabat); GGSISSdgY (SEQ ID NO: 413) (Chothia); GGSISSdgYYWS (SEQ ID NO: 414) (Estendida) YMYYSGSTYYNPS LKS (SEQ ID NO: 415) (Kabat); YYSGS (SEQ ID NO: 416) (Chothia) DFGWYFDL (SEQ ID NO: 417); Petition 870260028237, on 03 / 25 / 2026, page. 892 / 1082 72 / 230 Cadeia Pesada mAb CDRH1 CDRH2 CDRH3 12A2 SdgYYWS (SEQ ID NO: 418) (Kabat); GGSVSSdgY (SEQ ID NO: 419) (Chothia); GGSVSSdgYYWS (SEQ ID NO: 420) (Estendida) YIYYRRITDYNPSLKS (SEQ ID NO: 421) (Kabat); YYRRI (SEQ ID NO: 422) (Chothia) DFGWYFDL (SEQ ID NO: 423) 12C4 GYYLH (SEQ ID NO: 424) (Kabat); GYTFTGY (SEQ ID NO: 425) (Chothia); GYTFTGYYLH(SEQ ID NO: 426) (Estendida) WINpNSGGTNYAQKFQG (SEQ ID NO: 427) (Kabat); NpNSGG (SEQ ID NO: 428) (Chothia) DRGVtmivDGMDD (SEQ ID NO: 429) 12C5 DYGMH (SEQ ID NO: 430) (Kabat); GFTFSDY (SEQ ID NO: 431) (Chothia); GFTFSDYGMH (SEQ ID NO: 432) (Estendida) VIWYDGSnKYYADS VKG (SEQ ID NO: 433) (Kabat); WYDGSn (SEQ ID NO: 434) (Chothia) DEVGfvGAFDI (SEQ ID NO: 435) 12C6 DYGMH (SEQ ID NO: 663) (Kabat); GFTFSDY (SEQ ID NO: 664) (Chothia); GFTFSDYGMH (SEQ ID NO: 665) (Estendida) VIWYDGSnKYYADS VKG (SEQ ID NO: 666) (Kabat); WYDGSn (SEQ ID NO: 667) (Chothia) DEVGfvGAFDI (SEQ ID NO: 668) 12D3 SdgYYWS (SEQ ID NO: 436) (Kabat); GGSISSdgY (SEQ ID NO: 437) (Chothia);GGSISSdgYYWS (SEQ ID NO: 438) (Estendida) YMYYSGITYHNPSL KS (SEQ ID NO: 439) (Kabat); YYSGI (SEQ ID NO: 440) (Chothia) DFGWYFDL (SEQ ID NO: 441); Petition 870260028237, of 25 / 03 / 2026, p. 893 / 1082 73 / 230 Cadeia Pesada mAb CDRH1 CDRH2 CDRH3 12D6 SdaYYWS (SEQ ID NO: 442) (Kabat); GGSISSdaY (SEQ ID NO: 443) (Chothia); GGSISSdaYYWS (SEQ ID NO: 444) (Estendida) YMYYSGITYYNPSL KS (SEQ ID NO: 445) (Kabat); YYSGI (SEQ ID NO: 446) (Chothia) DFGWYFDL (SEQ ID NO: 447) 12D7 DYGIH (SEQ ID NO: 448) (Kabat); GFTFSDY (SEQ ID NO: 449) (Chothia); GFTFSDYGIH (SEQ ID NO: 450) (Estendida) VIWYDGSiKKYSDSVKG (SEQ ID NO: 451) (Kabat); WYDGSi (SEQ ID NO: 452) (Chothia) DEVGtfGAFDF (SEQ ID NO: 453) 12F5 NAWMS (SEQ ID NO: 454) (Kabat); GFTFSNA (SEQ ID NO: 455) (Chothia); GFTFSNAWMS (SEQ ID NO: 456) (Estendida) RIKsktGGGTTDYAAPVKG (SEQ ID NO: 457) (Kabat); KsktGGGT (SEQ ID NO: 458) (Chothia) LIVGaiSLFDY (SEQ ID NO: 459) 12H4 YYFWT (SEQ ID NO: 460) (Kabat); GGSISYY (SEQ ID NO: 461) (Chothia); GGSISYYFWT (SEQ ID NO: 462) (Estendida) QIYYSGNTNSNPSLKS (SEQ ID NO: 463) (Kabat); YYSGN (SEQ ID NO: 464) (Chothia) AEGSlDAFDI (SEQ ID NO: 465) 8C8 SYSMN (SEQ ID NO: 466) (Kabat); GFTFSSY (SEQ ID NO: 467) (Chothia);GFTFSSYSMN (SEQ ID NO: 468) (Estendida) SIStSSNYIHYADSL QG (SEQ ID NO: 469) (Kabat); StSSNY (SEQ ID NO: 470) (Chothia) DKGTtltnWYFDL (SEQ ID NO: 471) 8F7 SYGMH (SEQ ID NO: 472) (Kabat); GFTFSSY (SEQ ID NO: 473) (Chothia); GFTFSSYGMH (SEQ ID NO: 474) (Estendida) VIWYDGSnKYYADS LKG (SEQ ID NO: 475) (Kabat); WYDGSn (SEQ ID NO: 476) (Chothia) DGYSgssDAFDI (SEQ ID NO: 477); Petition 870260028237, on 03 / 25 / 2026, page. 894 / 1082 74 / 230 Cad eia Pesada mAb CDRH1 CDRH2 CDRH3 8F8 YYYWS (SEQ ID NO: 478) (Kabat); GGSISYY (SEQ ID NO: 479) (Chothia); GGSISYYYWS (SEQ ID NO: 480) (Estendida) NINYMGNTIYNPSLKS (SEQ ID NO: 481) (Kabat); NYMGN (SEQ ID NO: 482) (Chothia) AEGSlDAFDF (SEQ ID NO: 483) 9D8 GYYIY (SEQ ID NO: 484) (Kabat); GYIFTGY (SEQ ID NO: 485) (Chothia); GYIFTGYYIY (SEQ ID NO: 486) (Estendida) WINpSSGGTNYAQKFQG (SEQ ID NO: 487) (Kabat); NpSSGG (SEQ ID NO: 488) (Chothia) DRKReyyynFGMDV (SEQ ID NO: 489) 9E10 SHYIY (SEQ ID NO: 490) (Kabat); GYTFTSH (SEQ ID NO: 491) (Chothia); GYTFTSHYIY (SEQ ID NO: 492) (Estendida) WINpNSGGTNYAQKFQD (SEQ ID NO: 493) (Kabat); NpNSGG (SEQ ID NO: 494) (Chothia) DRKReyyynFGMDV (SEQ ID NO: 495) 9E5 SHYIY (SEQ ID NO: 496) (Kabat); GFTFTSH(SEQ ID NO: 497) (Chothia); GFTFTSHYIY (SEQ ID NO: 498) (Estendida) WINpNSGGTKYAQKFQD (SEQ ID NO: 499) (Kabat); NpNSGG (SEQ ID NO: 500) (Chothia) DRKReyyynFGMDV (SEQ ID NO: 501) 9F4 IYAIH (SEQ ID NO: 502) (Kabat); GFTLSIY (SEQ ID NO: 503) (Chothia);GFTLSIYAIH (SEQ ID NO: 504) (Estendido) SFGgRGSSTYFADS VKG (SEQ ID NO: 505) (Kabat); GgRGSS (SEQ ID NO: 506) (Chothia) EKDWgRGFDY (SEQ ID NO: 507) 9F8 NYSMN (SEQ ID NO: 508) (Kabat); GFTFSNY (SEQ ID NO: 509) (Chothia); GFTFSNYSMN (SEQ ID NO: 510) (Estendida) SISsSTIYIYYADSVKG (SEQ ID NO: 511) (Kabat); SsSTIY (SEQ ID NO: 512) (Chothia) DIGWevftLGFDY (SEQ ID NO: 513); Petition 870260028237, on 03 / 25 / 2026, page. 895 / 1082 75 / 230 Tabela 2B Cadeia Leve mAb CDRL1 CDRL2 CDRL3 31H1 RSSQSLVHSDGNTYLS (SEQ ID NO: 193); KISNRFS (SEQ ID NO: 194) MQATQFPLT (SEQ ID NO: 195) 63B2 RSSQSLVHSDGNTYLS (SEQ ID NO: 196); KISNRFS (SEQ ID NO: 197) MQATQFPLT (SEQ ID NO: 198) 40E3 RASQGISNYLA (SEQ ID NO: 199); AASSLQS (SEQ ID NO: 200) QQYNSYPLT (SEQ ID NO: 201) 42C3 RSSQSLVYSDENTYLN (SEQ ID NO: 202); QVSNRDS (SEQ ID NO: 203) MQGTYWPPT (SEQ ID NO: 204) 45F11 RASQSVSSSLA (SEQ ID NO: 205); GASTRAT(SEQ ID NO: 206) QQYINWPH (SEQ ID NO: 207) 64F9 QASQDISNYLN (SEQ ID NO: 208); GASNLET (SEQ ID NO: 209) QQYDNFPIT (SEQ ID NO: 210) 72C2 RASQSVSSNLA (SEQ ID NO: 211); SASTRAS (SEQ ID NO: 212) QQYDNWPPLT (SEQ ID NO: 213) 2F10 RASQSVSSSYLA (SEQ ID NO: 214); GASSRAT (SEQ ID NO: 215) QQYGSSPLT (SEQ ID NO: 216) 4F11 RASQDISNYLA (SEQ ID NO: 217); AASSLQS (SEQ ID NO: 218) LQLNSFPFT(SEQ ID NO: 219) 10H10 RASQGISSWLA (SEQ ID NO: 220); AASSLQS (SEQ ID NO: 221) QQAFSFPFT (SEQ ID NO: 222) 17G6 KSSQSVLYSYNNKNYVA (SEQ ID NO: 223);WASTRES (SEQ ID NO: 224) QQYYSTLT (SEQ ID NO: 225); Petition 870260028237, dated 03 / 25 / 2026, pp. 896 / 1082 76 / 230 Cadeia Leve mAb CDRL1 CDRL2 CDRL3 65E11 RASQSVSSSYLA (SEQ ID NO: 226); DASSRAT(SEQ ID NO: 227) QQYGSSPLT (SEQ ID NO: 228) P02B10 SGSSSNIGSNYVY (SEQ ID NO: 229); RNNQRPS (SEQ ID NO: 230) AAWDDSLSGVV (SEQ ID NO: 231) P07D03 SGSRSNIGSNYVY (SEQ ID NO: 232); RNNQRPS (SEQ ID NO: 233) ASWDGSLSAVV (SEQ ID NO: 234) P08A02 SGSSSNIGSNYVY (SEQ ID NO: 235); RNNQRPS (SEQ ID NO: 236) ATWDDSLGSPV (SEQ ID NO: 237) P08E02 RASQSISRYLN (SEQ ID NO: 238); AASILQT (SEQ ID NO: 239) QQSYSTTMWT (SEQ ID NO: 240) P08F08 SGSSSNIGSNYVN (SEQ ID NO: 241); GDYQRPS (SEQ ID NO: 242) ATRDDSLSGSVV (SEQ ID NO: 243) P08G02 RASQSIYDYLH (SEQ ID NO: 244); DASNLQS (SEQ ID NO: 245) QQSYTTPLFT (SEQ ID NO: 246) P12B09 RASQYIGRYLN (SEQ ID NO: 247); GATSLAS (SEQ ID NO: 248) QQSYSTTSPT (SEQ ID NO: 249) P12F02 SGSTSNIGRNYVY (SEQ ID NO: 250); RTNQRPS (SEQ ID NO: 251) AAWDDSLSGRV (SEQ ID NO: 252) P12G07 SGSSSNIGSNYVY (SEQ ID NO: 253); MNNQRPS (SEQ ID NO: 254) AAWDDSLSAVV (SEQ ID NO: 255) P13F04 SGSNSNIGTNYVS (SEQ ID NO: 256);RSSRRPS (SEQ ID NO: 257) AAWDGSLSGHWV (SEQ ID NO: 258) P15D02 RASQSIDTYLN (SEQ ID NO: 259); SASSLHS (SEQ ID NO: 260) QQSYSTTAWT (SEQ ID NO: 261) P16C05 RASQSIGQSLN (SEQ ID NO: 262); GASSLQS (SEQ ID NO: 263) QQSYSTPIT (SEQ ID NO: 264); Petition 870260028237, on 03 / 25 / 2026, page. 897 / 1082 77 / 230 Cadeia Leve mAb CDRL1 CDRL2 CDRL3 10A1 RASQSISTWLA (SEQ ID NO: 514); KASSLES (SEQ ID NO: 515) QQYKSYSHT (SEQ ID NO: 516) 10E2 RASQSISSWLA (SEQ ID NO: 517); KASSLES (SEQ ID NO: 518) QQYKSFSLT (SEQ ID NO: 519) 11A1 RASQSISSWLA (SEQ ID NO: 520); KASTLES (SEQ ID NO: 521) QQYNSYSYT (SEQ ID NO: 522) 11C1 RASQSVSSWLA (SEQ ID NO: 523); KASSLES (SEQ ID NO: 524) QQYNTYSHT (SEQ ID NO: 525) 11D1 RASQGIRNDLG (SEQ ID NO: 526); AASSLQS (SEQ ID NO: 527) LQDYNYPFT (SEQ ID NO: 528) 11E1 RASQDIDNYLA (SEQ ID NO: 529); AASALQS (SEQ ID NO: 530) QNYNSGPRT (SEQ ID NO: 531) 12A2 RASQDISNYLT (SEQ ID NO: 532); AASALQS (SEQ ID NO: 533) QNYNSAPRT (SEQ ID NO: 534) 12C4 RSSQSLLHSNGYNYLD (SEQ ID NO: 535); LGSNRAS (SEQ ID NO: 536) MQTLQTPFT (SEQ ID NO: 537) 12C5 RASQGINSHLA (SEQ ID NO: 538); YASTLPS (SEQ ID NO: 539) QQLNHYPIT (SEQ ID NO: 540) 12C6 RASQGINSHLA (SEQ ID NO: 669); YASTLPS (SEQ ID NO: 670) QQLNHYPIT (SEQ ID NO: 671) 12D3 RASQGISNYLA (SEQ ID NO: 541);AASTLHS (SEQ ID NO: 542) QKYNSAPRT (SEQ ID NO: 543) 12D6 RASQDISNYLA (SEQ ID NO: 544); AASTLHS (SEQ ID NO: 545) QKYNSAPRT (SEQ ID NO: 546) 12D7 RASQDISSFLA (SEQ ID NO: 547); VASTLQS (SEQ ID NO: 548) QQLHVYPIT (SEQ ID NO: 549); Petition 870260028237, on 03 / 25 / 2026, page. 898 / 1082 78 / 230 Cadeia Leve mAb CDRL1 CDRL2 CDRL3 12F5 RSSQSLLDSDDGNtYLD (SEQ ID NO: 550); TLSYRAS (SEQ ID NO: 551) MQRIEFPFT (SEQ ID NO: 552) 12H4 RASQTISTWLA (SEQ ID NO: 553); KASNLES (SEQ ID NO: 554) QQYQTFSHT (SEQ ID NO: 555) 8C8 RASQGISNYLA (SEQ ID NO: 556); AASTLQS (SEQ ID NO: 557) QKYNSAPLT (SEQ ID NO: 558) 8F7 RSSQTLVHSNGY NYLN (SEQ ID NO: 559); LGSNRAS (SEQ ID NO: 560) MQAIQTPYT (SEQ ID NO: 561) 8F8 RASQSISSWLA (SEQ ID NO: 562); KASNLES (SEQ ID NO: 563) QQYNSYSCT (SEQ ID NO: 564) 9D8 QASQDINNYLH (SEQ ID NO: 565); DASDWET (SEQ ID NO: 566) QQYDHLPIT (SEQ ID NO: 567) 9E10 QASQDISNYLH (SEQ ID NO: 568); DASDLET (SEQ ID NO: 569) QQYDHLPIT (SEQ ID NO: 570) 9E5 QASQDISNYLH (SEQ ID NO: 571); DASDLET (SEQ ID NO: 572) QQYDHLPIT (SEQ ID NO: 573) 9F4 QASQDISNYLN (SEQ ID NO: 574); DASNLET (SEQ ID NO: 575) QQYDNLPYT (SEQ ID NO: 576) 9F8 RSSQSLLYSNGYNYLD (SEQ ID NO: 577); LNSNRAS (SEQ ID NO: 578) MQALQTPLT (SEQ ID NO: 579)

[0189] The description encompasses modifications to CARs and polypeptides comprising the sequences indicated in Tables 1 or 2A-2B, including functionally equivalent CARs with modifications that do not significantly affect their properties and variants that have enhanced or reduced activity and / or affinity. For example, Petition 870260028237, dated 03 / 25 / 2026, page 899 / 1082 79 / 230 plo, the amino acid sequence can be mutated to obtain an antibody with the desired binding affinity for CD70. Polypeptide modification is routine practice in the art and does not need to be described in detail in this document. Examples of modified polypeptides include polypeptides with conservative substitutions of amino acid residues, one or more deletions or additions of amino acids that do not significantly alter the functional activity, or that mature (enhance) the affinity of the polypeptide for its ligand, or the use of chemical analogs.

[0190] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue or the antibody fused to an epitope label. Other variants of antibody molecule insertion include the fusion to the N- or C-terminal of the antibody of an enzyme or polypeptide that increases the antibody's half-life in the bloodstream.

[0191] Substitution variants have at least one amino acid residue in the antibody molecule removed and a different residue inserted in its place. Sites of greatest interest for substitutional mutagenesis include hypervariable regions, but FR alterations are also contemplated. Conservative substitutions are shown in Table 3 with the title Conservative Substitutions. If these substitutions result in a change in biological activity, then more substantial alterations, termed exemplary substitutions in Table 3, or as described below with reference to amino acid classes, can be introduced and the products selected. Petition 870260028237, dated 03 / 25 / 2026, pages 900 / 1082 80 / 230 Table 3: Amino Acid Substitutions Original Residue (naturally occurring amino acid) Conservative Substitutions Exemplary Substitutions Wing (A) Val Val; Leu; With Arg (R) Lys Lys; Gln; Asn Asn (N) Gln Gln; His; Asp, Lys; Arg Asp (D) Glu Glu; Asn Cys (C) Ser Ser; Only Gln (Q) Asn Asn; Glu Glu (E) Asp Asp; Gln Gly (G) Ala Ala His (H) Arg Asn; Gln; Lys; Arg Ile (I) Leu Leu; Val; But; No; Phe; Norleucine Leu (L) Ile Norleucine; Ile; Val; But; No; Phe Lys (K) Arg Arg; Gln; Donkey Met (M) Leu Leu; Faith; Ile Fe (F) Tyr Leu; Val; Ile; No; Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Ser Ser Trp (W) Tyr Tyr; Fe Tyr (Y) Phe Trp; Faith; Thr; Ser Val (V) Leu Ile; Leu; But; Phe; No; Norleucine

[0192] In some embodiments, the description provides a CAR comprising an extracellular ligand-binding domain that binds to CD70 and competes for binding to CD70 with a CAR described in this document, including a CAR comprising an extracellular domain comprising an ScFv comprising the sequences 31H1, 63B2, 40E3, 42C3, 45F11, 64F9, 72C2, 2F10, 4F11, 10H10, 17G6, 65E11, P02B10, P07D03, P08A02, P08E02, P08F08, P08G02, P12B09, P12F02, P12G07, P13F04, P15D02, P16C05, 10A1, 10E2, 11A1, 11C1, 11D1, 11E1, 12A2, 12C4, 12C5, 12D3, 12D6, 12D7, Petition 870260028237, dated 03 / 25 / 2026, pages 901 / 1082 81 / 230 12F5, 12H4, 8C8, 8F7, 8F8, 9D8, 9E10, 9E5, 9F4 or 9F8.

[0193] In some embodiments, the description provides a CAR, which specifically binds to CD70, wherein the CAR comprises a VH region comprising a sequence indicated in SEQ ID NO: 20; and / or a VL region comprising a sequence indicated in SEQ ID NO: 19. In some embodiments, the description provides a CAR, which specifically binds to CD70, wherein the CAR comprises a VH region comprising a sequence indicated in SEQ ID NO: 22; and / or a VL region comprising a sequence indicated in SEQ ID NO: 21. In some embodiments, the description provides a CAR, which specifically binds to CD70, wherein the CAR comprises a VH region comprising a sequence indicated in SEQ ID NO: 28; and / or a VL region comprising a sequence indicated in SEQ ID NO: 27.In some embodiments, the description provides a CAR, which specifically binds to CD70, wherein the CAR comprises a VH region comprising a sequence indicated in SEQ ID NO: 36; and / or a VL region comprising a sequence indicated in SEQ ID NO: 35. In some embodiments, the description provides a CAR, which specifically binds to CD70, wherein the CAR comprises a VH region comprising a sequence indicated in SEQ ID NO: 46; and / or a VL region comprising a sequence indicated in SEQ ID NO: 45. In some embodiments, the description provides a CAR, which specifically binds to CD70, wherein the CAR comprises a VH region comprising a sequence indicated in SEQ ID NO: 18; and / or a VL region comprising a sequence indicated in SEQ ID NO: 17.In some embodiments, the description provides a CAR, which specifically links to CD70, wherein the CAR comprises a VH region comprising a sequence indicated in SEQ ID NO: 34; and / or a VL region comprising a sequence indicated in SEQ ID. Petition 870260028237, dated 03 / 25 / 2026, pages 902 / 1082 82 / 230 NO: 33. In some embodiments, the description also provides CARs comprising CDR portions of antibodies for CD70 antibodies based on CDR contact regions. CDR contact regions are regions of an antibody that imbue the antibody with specificity for an antigen. In general, CDR contact regions include residue positions in CDR and Vernier zones that are constrained in order to maintain the proper loop structure for the antibody to bind a specific antigen. See, for example, Makabe et al., J. Biol. Chem., 283:1156-1166, 2007. The determination of CDR contact regions is within the art.

[0194] The binding affinity (KD) of the binding domain to the specific CAR ligand for CD70, as described in this document, to CD70 (such as human CD70) may be, for example, about 0.1 to about 1000 nM, for example, between about 0.5nM to about 500nM, or, for example, between about 1nM to about 250nM. In some embodiments, the binding affinity is approximately any value between 1000 nm, 750 nm, 500 nm, 400 nm, 300 nm, 250 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 45 nm, 40 nm, 35 nm, 30 nm, 25 nm, 20 nm, 19 nm, 18 nm, 17 nm, 16 nm, 15 nm, 10 nm, 8 nm, 7.5 nm, 7 nm, 6.5 nm, 6 nm, 5.5 nm, 5 nm, 4 nm, 3 nm, 2 nm, 1 nm, 0.5 nm, 0.3 nm, or 0.1 nm.

[0195] In some embodiments, the binding affinity (KD) of the scFv binding domain to the specific CAR ligand for CD70, as described in this document, to CD70, is about 10nM to about 100nM, about 10nM to about 90nM, about 10nM to about 80nM, about 20nM to about 70nM, about 25nM to about 75nM, or about 40nM to about 110nM. In some embodiments, the scFv binding affinities described in this paragraph are for human CD70.

[0196] In some modalities, the binding affinity is lower Petition 870260028237, dated 03 / 25 / 2026, pp. 903 / 1082 83 / 230 which is approximately any value between 1000 nm, 900 nm, 800 nm, 250 nm, 200 nm, 100 nm, 50 nm, 30 nm, 20 nm, 10 nm, 7.5 nm, 7 nm, 6.5 nm, 6 nm, 5 nm.

[0197] The intracellular signaling domain of a CAR, as described, is responsible for intracellular signaling after the extracellular ligand-binding domain binds to the target, resulting in immune cell activation and an immune response. The intracellular signaling domain has the ability to activate at least one of the normal effector functions of the immune cell in which the CAR is expressed. For example, the effector function of a T cell may be cytolytic activity or helper activity, including cytokine secretion.

[0198] In some embodiments, an intracellular signaling domain for use in a CAR may be the cytoplasmic sequences of, for example, without limitation, the T cell receptor and coreceptors that act together to initiate signal transduction after antigen receptor binding, as well as any derivative or variant of these sequences and any synthetic sequence having the same functional capability. Intracellular signaling domains comprise two distinct classes of cytoplasmic signaling sequences: those that initiate primary antigen-dependent activation and those that act independently of antigen to provide a secondary or co-stimulatory signal. Primary cytoplasmic signaling sequences may comprise signaling motifs that are known as ITAM tyrosine-based immunoreceptor activation motifs.ITAMs are well-defined signaling motifs found in the intracytoplasmic tail of a variety of receptors that serve as binding sites for syk / zap70 class tyrosine kinases. Examples of ITAMs used in the description may include, but are not limited to, examples derived from TCRZ, FcRY, FcRe, FcRε, CD3y, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, and... Petition 870260028237, dated 03 / 25 / 2026, pp. 904 / 1082 84 / 230 CD66d. In some embodiments, the intracellular signaling domain of the CAR may comprise the CD3Z signaling domain that has an amino acid sequence with at least about 70%, at least 80%, at least 90%, 95%, 97%, or 99% sequence identity with an amino acid sequence indicated in SEQ ID NO: 272 or 683. In some embodiments, the intracellular signaling domain of the CAR described comprises a co-stimulatory molecule domain.

[0199] In some embodiments, the intracellular signaling domain of a CAR from the description comprises a part of the co-stimulatory molecule selected from the group consisting of a 41BB fragment (GenBank: AAA53133) and CD28 (NP_006130.1). In some embodiments, the intracellular signaling domain of the CAR from the description comprises an amino acid sequence that comprises at least 70%, at least 80%, at least 90%, 95%, 97%, or 99% sequence identity with an amino acid sequence indicated in SEQ ID NO: 271 or 682 and SEQ ID NO: 275.In some embodiments, the intracellular signaling domain of the CAR description comprises an amino acid sequence that has at least 70%, at least 80%, at least 90%, 95%, 97%, or 99% sequence identity with an amino acid sequence indicated in SEQ ID NO: 271 or 682 and / or at least 70%, at least 80%, at least 90%, 95%, 97%, or 99% sequence identity with an amino acid sequence indicated in SEQ ID NO: 276.

[0200] CARs are expressed on the cell surface membrane. Thus, a CAR may comprise a transmembrane domain. Transmembrane domains suitable for a CAR disclosed in this document have the ability to (a) be expressed on the surface of a cell which, in some embodiments, is an immune cell such as, for example, without limitation, a lymphocytic cell, such as a Petition 870260028237, dated 03 / 25 / 2026, pp. 905 / 1082 85 / 230 T helper (Th) cells, cytotoxic (Tc) cells, regulatory (Treg) cells, or natural killer (NK) cells and / or (b) interact with the ligand-binding domain and intracellular signaling domain to direct the cellular response of an immune cell against a predefined target cell. The transmembrane domain can be derived from a natural or synthetic source. The transmembrane domain can be derived from any membrane-bound or transmembrane protein. As non-limiting examples, the transmembrane polypeptide can be a subsequence or subunit of a T cell receptor such as α, β, γ, or δ, a polypeptide consisting of a CD3 complex, IL-2 receptor p55 (α chain), p75 (β chain), or γ chain, Fc receptor subunit chain, in particular Fcy receptor III or CD proteins. Alternatively, the transmembrane domain can be synthetic and may predominantly comprise hydrophobic residues such as leucine and valine.In some embodiments, the aforementioned transmembrane domain is derived from the human CD8α chain (e.g., NP_001139345.1). The transmembrane domain may further comprise a stalk domain between the extracellular ligand-binding domain and the aforementioned transmembrane domain. A stalk domain may comprise up to 300 amino acids—in some embodiments, 10 to 100 amino acids or, in some embodiments, 25 to 50 amino acids. The stalk region may be derived from all or part of naturally occurring molecules, such as all or part of the extracellular region of CD8, CD4, CD28, 41BB, or IgG (in particular, the hinge region of an IgG), or from all or part of a constant region of an antibody heavy chain. Alternatively, the stalk domain may be a synthetic sequence that corresponds to a naturally occurring stalk sequence, or it may be an entirely synthetic stalk sequence.In some embodiments, the aforementioned stalk domain is a part of the human CD8α chain (e.g., NP_001139345.1). In another embodiment, part. Petition 870260028237, dated 03 / 25 / 2026, pp. 906 / 1082 86 / 230 cular, the aforementioned hinge and transmembrane domains comprise a portion of the human CD8a chain which, in some embodiments, comprises at least 70%, at least 80%, at least 90%, 95%, 97%, or 99% sequence identity with amino acid sequences selected from the group consisting of SEQ ID NO: 268 and 270. In some embodiments, the stalk domain of the CARs described herein comprises a CD8a subsequence, an IgG1, or an FcyRII^, in particular the hinge region of any of CD8α, IgG1, or FcyRII^. In some embodiments, the stalk domain comprises a human CD8α hinge, a human IgG1 hinge, or a human FcyRII^ hinge. In some embodiments, the CARs disclosed herein may comprise an extracellular ligand-binding domain that specifically binds to CD70.In some embodiments, the CARs disclosed in this document comprise an scFv, human hinge and transmembrane domains of CD8α, a CD3Z signaling domain, and a 4-1BB signaling domain.

[0201] Table 4 provides exemplary sequences of domains that can be used in the CARs disclosed in this document. Table 4: Exemplary Sequences of CAR Components Domain Amino Acid Sequence SEQ ID NO: CD8α signal peptide MALPVTALLLPLALLLHAARP 266 FcvRIIto hinge GLAVSTISSFFPPGYQ ​​​​267 CD8α hinge TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD 268 IgG1 hinge EPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS- TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS- LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 269 Petition 870260028237, dated 03 / 25 / 2026, pp. 907 / 1082 87 / 230 Domain Amino Acid Sequence SEQ ID NO: CD8a transmembrane domain (TM) IYIWAPLAGTCGVLLLSLVITLYC 270 41BB intracellular signaling domain (ISD) KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 271 41BB intracellular signaling domain (ISD) GRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL 682 CD3Z intracellular signaling domain (ISD) RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 272 CD3Z intracellular signaling domain (ISD) RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 683 FcεRI α-TM-IC (transmembrane and intracellular domain of FcεRI α chain) FFIPLLVVILFAVDTGLFISTQQQVTFLLKIKRTRKGFRLLNPHPKPNPKNN 273 FcεRIβ-ΔITAR (FcεRI β chain without ITAM) MDTESNRRANLALPQEPSSVPAFEVLEIS- PQEVSSGRLLKSASSPPLHTWLTVLKKEQEFLGVTQILTAMICLCFGTVVCSVLDISHIEGDIFSSFKAGYPFWGAIFFSISGMLSIISERRNATYLVRGSLGANTASSIAGGTGITI LIINLKKSLAYIHIHSCQKFFETKCFMASFSTEIVVMMLFLTILGLGSAVSLTI- CGAGEELKGNKVPE 274 CD28-IC (CD28 costimulatory domain) RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 276 FcεRIγ-SP (signal peptide) MIPAVVLLLLLLVEQAAA 277 FcεRI γ-ΔΙΤΑΡ (FcεRI γ chain without ITAM) LGEPQLCYILDAILFLYGIVLTLLYCRLKIQVRKAAITSYEKS 278 GSG-P2A (GSG-P2A ribosomal skipping polypeptide) GSGATNFSLLKQAGDVEENPGP 279 GSG-T2A (skipping polypeptide ribosomal GSG-T2A) GSGEGRGSLLTCGDVEENPGP 280

[0202] Downregulation or mutation of target antigens is commonly observed in cancer cells, creating antigen loss escape variants. Thus, to compensate for tumor escape and make the immune cell more target-specific, the specific CAR Petition 870260028237, dated 03 / 25 / 2026, pages 908 / 1082 The 88 / 230 for CD70 may comprise one or more additional extracellular ligand-binding domains to simultaneously bind different elements in the target, thereby enhancing immune cell activation and function. In some embodiments, the extracellular ligand-binding domains may be tandemly placed on the same transmembrane polypeptide and, optionally, may be separated by a peptide linker. In some embodiments, said different extracellular ligand-binding domains may be placed on different transmembrane polypeptides that comprise the CAR. In some embodiments, the description refers to a population of CARs, each CAR comprising a different extracellular ligand-binding domain.In particular, the description refers to a method for manipulating immune cells comprising providing an immune cell and expressing on the cell surface a population of CARs, each CAR comprising different extracellular ligand-binding domains. In another particular embodiment, the description refers to a method for manipulating an immune cell comprising providing an immune cell and introducing into the cell polynucleotides encoding polypeptides that comprise a population of CARs, each comprising different extracellular ligand-binding domains. A population of CARs is understood to be at least two, three, four, five, six or more CARs, each comprising different extracellular ligand-binding domains. The different extracellular ligand-binding domains according to the description can, in some embodiments, simultaneously bind different elements on the target, thus enhancing the activation and function of the immune cell.The description also refers to an isolated immune cell comprising a population of CARs, each comprising different extracellular ligand-binding domains.

[0203] In another aspect, the description provides polynucleotides that Petition 870260028237, dated 03 / 25 / 2026, pp. 909 / 1082 89 / 230 encode any of the CARs and polypeptides described in this document. The polynucleotides can be made and expressed by procedures known in the art.

[0204] In another aspect, the description provides compositions (such as pharmaceutical compositions) comprising any of the cells in the description. In some embodiments, the composition comprises a cell comprising a polynucleotide encoding any of the CARs described in this document. In still other embodiments, the composition comprises one or both of the polynucleotides indicated in SEQ ID NO: 297 and SEQ ID NO:298, SEQ ID NO: 299 and SEQ ID NO:300, SEQ ID NO: 301 and SEQ ID NO:302, SEQ ID NO: 303 and SEQ ID NO:304, SEQ ID NO: 305 and SEQ ID NO: 306, SEQ ID NO: 307 and SEQ ID NO: 308 or SEQ ID NO: 309 and SEQ ID NO:310, below: Variable region of heavy chain 4F11 CAGGTCACCTTGAAGGAGTCTGGTCCTGTGCTGGTGAAACCCACAGAGACCCTCACGCTGACCTGCACCGTCTCTGGGTTCTCACTCAGTAATGCTAGAATGGGTGTGACCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGGAGTGGCTTGCACACATTTTTTCGAATGACGAAAAATCCTACAGTACATCTCTGAAGAGCAGGCTCACCATCTCCAAGGACACTTCCAAAACCCAGGTGGTCCTTACCATGACCAACATGGACCCTGTGGACACAGCCACATATTACTGTGCACGGATACGAGATTACTATGACATTAGTAGTTATTATGACTACTGGGGCCAGGGAACCCTGGTCAGCGTCTCCTCA (SEQ ID NO: 297) Região variável de cadeia leve de 4F11 GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGACATTAGCAATTATTTAGCCTGGTTTCAGCAGAAACCAGGGAAAGTCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCGGGGACAGAAPetição 870260028237, de 25 / 03 / 2026, pág. 910 / 1082 90 / 230 TTCACTCTCACAATCAGCAGCCTGCTGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCTTAATAGTTTCCCGTTCACTTTTGGCGGAGGGACCAAGGTGGAGATCAAC (SEQ ID NO: 298)

[0205] In other embodiments, the composition comprises one or both of the polynucleotides indicated in SEQ ID NO: 299 and SEQ ID NO: 300 below: 17G6 heavy chain variable region GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTTAGTAGTTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAGCATAAAGCAAGATGGAAGTGAGAAATACTATGTGGAC TCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCAGTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGGTGTGTATTACTGTGCGAGAGAAGGAGTCAACTGGGGATGGAGACTCTACTGGCACTTCGATCTCTGGGGCCGTGGAACCCTGGTCACTGTCTCCTCA (SEQ ID NO: 299) 17G6 light chain variable region GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTACAACAATAAGAACTACGTAGCTTGGTACCAGCAGAAACCAGGACAACCTCCTAACCTACTCATTTTCTGG GCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTACTACTGTCAGCAATATTATAGTACGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 300).

[0206] In other embodiments, the composition comprises one or both of the polynucleotides indicated in SEQ ID NO: 301 and SEQ ID NO: 302 below: Petition 870260028237, dated 03 / 25 / 2026, pp. 911 / 1082 91 / 230 10H10 heavy chain variable region GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGTCTCTGGATTCACCTTCAGTAACCATAACATACACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTCGAAGTAGTAGTACCATATATT ACGCAGACTCTGTGAAGGGCCGATTCACAATCTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGACGAAGACACGGCTGTGTATTACTGTGCGAGAGATCACGCTCAGTGGTACGGTATGGACGTTTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 301). Variable region of the 10H10 light chain GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCGGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCAACAGGCTTTCAGTTTCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA (SEQ ID NO: 302).

[0207] In other embodiments, the composition comprises one or both of the polynucleotides indicated in SEQ ID NO: 303 and SEQ ID NO: 304 below: Variable region of heavy chain of P07D03 GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATATCGCTTCACAAGTTACTGGATAGGGTGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATG GGCTCTATATATCCTGATGATTCCGACACACGTTATAGCCCAAGCTTTCAGGGCCAGGTCACAATCAGCGCTGACAAGAGCATCAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACPetition 870260028237, of 25 / 03 / 2026, p. 912 / 1082 92 / 230 TACTGCGCCTCTAGCACAGTTGACTACCCGGGATACAGTTACTTCGACTACTGGGGCCAAGGTACACTGGTCACCGTTCAGCAGC (SEQ ID NO: 303) Light chain variable region of P07D03 GAGCTCCAGAGCGTGCTGACCCAGCCTCCTAGCGCAAGCGGCACCCCTGGACAGCGTGTGACAATTAGCTGTAGCGGAAGTCGTAGCAATATCGGATCAAACTATGTGTATTGGTATCAGCAATTGCCCGGTACAGCACCCAAATTGTCATATATAGAAATATCAG AGACCTAGCGGAGTGCCTGATCGTTTTAGCGGTAGCAAAAGCGGCACCAGCGCATCACTGGCAATTTCAGGCCTGCGTAGCGAAGATGAGGCGGATTATTACTGTGCGAGTTGGGATGGTTCGCTGAGTGCTGTTGTGTTCGGCACCGGTACAACTGACCGTTCTG (SEQ ID NO: 304)

[0208] In other embodiments, the composition comprises one or both of the polynucleotides indicated in SEQ ID NO: 305 and SEQ ID NO: 306 below: Heavy chain variable region of P08G02 GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATACACCTTTCCTTCATCATGGATAGGTTGGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATGGGCATCATATACCCTGATACTAGCCATACCCGTTACAGCCCAAGC TTTCAGGGCCAGGTCACAATCAGCGCTGACAAGAGCATCAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACTACTGTGCCCGTGCGAGCTATTTCGATCGTGGAACAGGGTATAGTTCTTGGTGGATGGATGTGTGGGGCCAAGGTACACTGGTCACCGTCAGCAGC (SEQ ID NO: 305) Variable light chain region of P08G02 GAGCTCGATATTCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCAAGCGTGGGCGATAGAGTGACCATTACCTGTAGGGCCTCACAAPetition 870260028237, dated 03 / 25 / 2026, page 913 / 1082 93 / 230 TCCATATACGACTATTTGCACTGGTATCAGCAGAAACCCGGGAAAGCACCCAAACTGCTGATTTACGATGCTTCCAACCTACAGTGGCGTTCCTTCACGTTTTAGCGGTAGCGGTTCAGGCACCGATTTACCCCTGACCATTAGCAGCCTTCAGCCCGAAGATTTCGCTACGTATTATTGCCAGCAATCATACACCACGCCGTTGTTTACATTCGGCCAGGGTACCAAAGTGGAAATCAAA (SEQ ID NO: 306)

[0209] In other embodiments, the composition comprises one or both of the polynucleotides indicated in SEQ ID NO: 307 and SEQ ID NO: 308 below: Heavy chain variable region of P08F08 GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATACGGATTCACAAGTTATTGGATAGGTTGGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATGGGTATCATTCATCCCGATGATAGCGACACCAAATACAGC CCAAGCTTTCAGGGCCAGGTCACAATCAGCGCTGACAAGAGCATCAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACTACTGTGCCTCTAGCTATTTGCGTGGCTTGTGGGGAGGCTATTTTGACTATTGGGGCCAAGGTACACTGGTCACCGTCAGCAGC (SEQ ID NO: 307) Light chain variable region of P08F08 GAGCTCCAGAGCGTGCTGACCCAGCCTCCTAGCGCAAGCGGCACCCCTGGACAGCGTGTGACAATTAGCTGTAGCGGATCAAGCTCAAACATTGGCTCAAATTATGTGAATTGGTATCAGCAATTGCCCGGTACAGCACCCAAACTGCTCATTTATGGAGATTATCAAC GACCTAGCGGAGTGCCTGATCGTTTTAGCGGTAGCAAAAGCGGCACCAGCGCATCACTGGCAATTTCAGGCCTGCGTAGCGAAGATGAGGCGGATTATTACTGTGCTACCCGCGACGATTCGTTATCTGGGTCTGTCGTTTTTGGCACCGGTACAAAACTGACCGTGCTG (SEQ ID NO: 308)

[0210] In other modalities, the composition includes Petition 870260028237, dated 03 / 25 / 2026, pp. 914 / 1082 94 / 230 one or both of the polynucleotides indicated in SEQ ID NO: 309 and SEQ ID NO: 310 below: Variable region of the heavy chain of P15D02 GAAGTGCAGCTTGTCCAGAGCGGAGCCGAAGTGAAGAAGCCTGGCGAGAGCCTGAAGATCAGCTGCAAGGGCTCCGGATACAGTTTTGCCTCATACTGGATCGGTTGGGTGCGCCAGATGCCTGGTAAGGGACTGGAATGGATGGGCGTAATTTACCCCGGAACTAGCGAGACACGTTACAGC CCAAGCTTTCAGGGCCAGGTCACAATCAGCGCTGACAAGAGCATCAGCACCGCCTACCTTCAGTGGTCGTCTCTGAAGGCCAGCGACACCGCAATGTACTACTGCGCTAAAGGGTTGAGTGCGAGTGCAAGTGGATATTCTTTCCAATATTGGGGCCAAGGTACACTGGTCACCGTCAGCAGC (SEQ ID NO: 309) Variable light chain region of P15D032 GAGCTCGATATTCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCAAGCGTGGGCGATAGAGTGACCATTACCTGTAGGGCCTCACAAAGCATCGACATATTTAAACTGGTATCAGCAGAAACCCGGGAAAGCACCCAAACTGCTGATTTATTCAGCTAGTAGCCTACACAGTGGCGTTCCTTCACGTTTTAGCGGTAGCGGTTCAGGCACCGATTTCACCCTGACCATTAGCAGCCTTCAGCCCGAAGATTTCGCTACGTATTATTGCCAACAATCATACAGCACAACTGCTTGGACATTCGGCCAGGGTACCAAAGTGGAAATCAAA (SEQ ID NO: 310)

[0211] Expression vectors and administration of polynucleotide compositions are described in this document.

[0212] In another aspect, the description provides a method for producing any of the polynucleotides described in this document.

[0213] Polynucleotides complementary to any sequences are also covered by this description. Polynucleotides can be single-stranded (coding or antisense) or double-stranded and can be DNA molecules (genomic, cDNA, or synthetic) or Petition 870260028237, dated 03 / 25 / 2026, pp. 915 / 1082 95 / 230 RNA. RNA molecules include HnRNA molecules, which contain introns and correspond to a DNA molecule in a one-to-one manner, and mRNA molecules, which do not contain introns. Additional coding or non-coding sequences may, but do not have to, be present within a polynucleotide of the description, and a polynucleotide may, but does not have to, be linked to other molecules and / or support materials.

[0214] Polynucleotides may comprise a native sequence (i.e., an endogenous sequence encoding an antibody or a portion thereof) or may comprise a variant of this sequence. Polynucleotide variants contain one or more substitutions, additions, deletions, and / or insertions such that the immunoactivity of the encoded polypeptide is not diminished relative to a native immunoreactive molecule. The effect on the immunoreactivity of the encoded polypeptide can generally be assessed as described in this document. Variant embodiments exhibit at least about 70% identity, at least about 80% identity, at least about 90% identity, or at least about 95% identity with a polynucleotide sequence encoding a native antibody or a portion thereof.

[0215] Two polynucleotide or polypeptide sequences are considered identical if the nucleotide or amino acid sequence in the two sequences is the same when aligned for maximum match, as described below. Comparisons between two sequences are typically performed by comparing the sequences within a comparison window to identify and compare local regions of sequence similarity. A comparison window, as used in this document, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75 or 40 to about 50, in which a sequence can be compared to Petition 870260028237, dated 03 / 25 / 2026, pp. 916 / 1082 96 / 230 is a reference sequence with the same number of contiguous positions after the two sequences have been optimally aligned.

[0216] The ideal alignment of sequences for comparison can be performed using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using standard parameters. This program incorporates several alignment schemes described in the following references: Dayhoff, MO, 1978, A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, MO (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J., 1990, Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, DG and Sharp, PM, 1989, CABIOS 5:151-153; Myers, EW and Muller W., 1988, CABIOS 4:11-17; Robinson, E.D., 1971, Comb. Teor. 11:105; Santou, N., Nes, M., 1987, Mol. Biol. Evol. 4:406-425; Sneath, P.H.A. e Sokal, R.R., 1973, Numeric Taxonomy the Principles and Practice of Numeric Taxonomy, Freeman Press, São Francisco, CA; Wilbur, W.J. e Lipman, D.J., 1983, Proc. Natl. Acad. Sci. EUA 80:726-730.

[0217] The percentage of sequence identity is determined by comparing two ideally aligned sequences along a comparison window of at least 20 positions, where the portion of the polynucleotide or polypeptide sequence in the comparison window may include additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, compared to the reference sequences (which do not comprise additions or deletions) for the ideal alignment of the two sequences. The percentage is calculated by determining the number of positions where identical nucleic acid bases or amino acid residues occur in both sequences to yield the number Petition 870260028237, dated 03 / 25 / 2026, pp. 917 / 1082 97 / 230 of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the sequence identity percentage.

[0218] Variants may also, or alternatively, be substantially homologous to a native gene, or a portion or complement thereof. Such polynucleotide variants are capable of hybridizing under moderately stringent conditions to a naturally occurring DNA sequence encoding a native antibody (or a complementary sequence).

[0219] Suitable moderately stringent conditions include pre-washing in a solution of 5X SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridization at 50°C-65°C, 5X SSC, overnight; followed by double washing at 65°C for 20 minutes each with 2X, 0.5X and 0.2X SSC containing 0.1% SDS.

[0220] As used in this document, highly stringent conditions or high stringency conditions are those that: (1) employ low ionic strength and high temperature for washing, for example, 0.015 M sodium chloride / 0.0015 M sodium citrate / 0.1% sodium dodecyl sulfate at 50 °C; (2) employ, during hybridization, a denaturing agent such as formamide, for example, 50% (v / v) formamide with 0.1% bovine serum albumin / 0.1% Ficoll / 0.1% polyvinylpyrrolidone / 50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42 °C; or (3) employs 50% formamide, 5x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5x Denhardt's solution, sonicated salmon sperm DNA (50 pg / ml), 0.1% SDS and 10% dextran sulfate at 42°C, with washes at 42°C in 0.2x SSC (sodium chloride). Petition 870260028237, dated 03 / 25 / 2026, pp. 918 / 1082 98 / 230 sodium dio / citrate) and 50% formamide at 55°C, followed by a high-rigor wash consisting of 0.1 x SSC containing EDTA at 55°C. Those skilled in the art will recognize how to adjust the temperature, ionic strength, etc., as needed to accommodate factors such as probe length and the like.

[0221] It will be appreciated by those skilled in the art that, as a result of the degeneracy of the genetic code, there are many nucleotide sequences that encode a polypeptide as described in this document. Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. However, polynucleotides that vary due to differences in codon usage are specifically contemplated by the description. Furthermore, alleles of the genes comprising the polynucleotide sequences provided in this document are within the scope of the description. Alleles are endogenous genes that are altered as a result of one or more mutations, such as deletions, additions, and / or nucleotide substitutions. The resulting mRNA and protein may, but do not necessarily, have an altered structure or function. Alleles can be identified using standard techniques (such as hybridization, amplification, and / or database sequence comparison).

[0222] The polynucleotides described herein can be obtained using chemical synthesis, recombinant methods, or PCR. Methods of chemical polynucleotide synthesis are well known in the art and need not be described in detail in this document. One skilled in the art may use the sequences provided in this document and a commercial DNA synthesizer to produce a desired DNA sequence.

[0223] For the preparation of polynucleotides using recombinant methods, a polynucleotide comprising a desired sequence can be inserted into a suitable vector and the vector, by its Petition 870260028237, dated 03 / 25 / 2026, pp. 919 / 1082 99 / 230 times, it can be introduced into a suitable host cell for replication and amplification, as further discussed in this document. Polynucleotides can be inserted into host cells by any means known in the art. Cells are transformed by introducing an exogenous polynucleotide through direct uptake, endocytosis, transfection, F-mating, or electroporation. Once introduced, the exogenous polynucleotide can be maintained within the cell as a non-integrated vector (such as a plasmid) or integrated into the host cell genome. The then amplified polynucleotide can be isolated from the host cell by methods well known in the art. See, for example, Sambrook et al. 1989.

[0224] Alternatively, PCR allows the reproduction of DNA sequences. PCR technology is well known in the art and is described in US Patents Nos. 4,683,195, 4,800,159, 4,754,065 and 4,683,202, as well as PCR: The Polymerase Chain Reaction, Mullis et al. eds., Birkauswer Press, Boston, 1994.

[0225] RNA can be obtained by using the isolated DNA in an appropriate vector and inserting it into a suitable host cell. When the cell replicas and the DNA are transcribed into RNA, the RNA can then be isolated using methods well known to those skilled in the art, as set out in Sambrook et al., 1989, above, for example.

[0226] Suitable cloning vectors can be constructed according to standard techniques or can be selected from a large number of cloning vectors available in the art. Although the selected cloning vector may vary according to the intended host cell, useful cloning vectors will generally have the ability to self-replicate, may possess a single target for a specific restriction endonuclease, and / or may Petition 870260028237, dated 03 / 25 / 2026, pp. 920 / 1082 100 / 230 transport genes to a marker that can be used in the selection of clones containing the vector. Suitable examples include plasmids and bacterial viruses, for example, PuC18, PuC19, Bluescript (e.g., pBS SK+) and derivatives thereof, mp18, mp19, pBR322, pMB9, Cole1, Pcr1, RP4, phage DNAs, and shuttle-type vectors such as Psa3 and Pat28. These and many other cloning vectors are available from commercial suppliers such as BiOrad, Strategene, and Invitrogen.

[0227] Expression vectors are generally replicable polynucleotide constructs containing a polynucleotide as described. It is essential that an expression vector be replicable in host cells either as episomes or as an integral part of chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, viral vectors, including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and expression vector(s) disclosed in PCT Publication No. WO 87 / 04462 or the pLVX lentiviral vector made available by Clonetech. Vector components may generally include, but are not limited to, one or more of the following: a signal sequence; an origin of replication; one or more marker genes; suitable transcriptional control elements (such as promoters, enhancers, and terminators).For expression (i.e., translation), one or more translational control elements are also typically required, such as ribosome binding sites, translation initiation sites, and stop codons.

[0228] Vectors containing the polynucleotides of interest can be introduced into the host cell by any of a number of suitable methods, including electroporation; transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microprojectile bombardment; lipoinfection; and infection (e.g., where the vector is an infectious agent, such as a virus). Petition 870260028237, dated 03 / 25 / 2026, pp. 921 / 1082 101 / 230 vaccinia). The choice of introducing vectors or polynucleotides will often depend on the resources of the host cell.

[0229] A polynucleotide encoding a specific CAR for The CD70 disclosed in this document may exist in an expression cassette or expression vector (e.g., a plasmid for introduction into a bacterial host cell or a viral vector, such as a baculovirus vector for transfection of an insect host cell, or a viral plasmid or vector, such as a lentivirus for transfection of a mammalian host cell). In some embodiments, a polynucleotide or vector may include a nucleic acid sequence encoding ribosomal skip sequences such as, for example, without limitation, a sequence encoding a 2A peptide. The 2A peptides, which have been identified in the Aphthovirus subgroup of picornaviruses, cause a ribosomal jump from one codon to the next without the formation of a peptide bond between the two amino acids encoded by the codons (see (Donnelly and Elliott 2001; Atkins, Wills et al. 2007; Doronina, Wu et al. 2008)).A codon is understood to be three nucleotides in an mRNA (or in the sense strand of a DNA molecule) that are translated by a ribosome into an amino acid residue. Thus, two polypeptides can be synthesized from a single, contiguous, open reading frame within an mRNA when the polypeptides are separated by a 2A oligopeptide sequence that lies within the frame. Such ribosomal hopping mechanisms are well known in the art and are known to be used by various vectors for the expression of various proteins encoded by a single messenger RNA.

[0230] To direct transmembrane polypeptides to the secretory pathway of a host cell, in some embodiments, a secretory signal sequence (also known as a leader sequence, pre-pro sequence, or presequence) is provided in a sequence Petition 870260028237, dated 03 / 25 / 2026, pp. 922 / 1082 102 / 230 polynucleotide or vector sequence. The secretory signal sequence is operationally linked to the transmembrane nucleic acid sequence, i.e., the two sequences are joined in the correct reading frame and are positioned to direct the newly synthesized polypeptide to the secretory pathway of the host cell. Secretory signal sequences are commonly positioned 5' to the nucleic acid sequence encoding the polypeptide of interest, although certain secretory signal sequences may be positioned elsewhere in the nucleic acid sequence of interest (see, for example, Welch et al., US Patent No. 5,037,743; Holland et al., US Patent No. 5,143,830). In some embodiments, the signal peptide comprises the amino acid sequence indicated in SEQ ID NO: 266 or 277. Those skilled in the art will recognize that, in view of the degeneracy of the genetic code, considerable sequence variation is possible among these polynucleotide molecules.In some embodiments, nucleic acid sequences from the description are codon-optimized for expression in mammalian cells or, in some embodiments, for expression in human cells. Codon optimization refers to the exchange in a sequence of interest of codons that are generally rare in highly expressed genes of a given species for codons that are generally frequent in highly expressed genes of such species, where such codons encode amino acids such as the codons being exchanged. Specific antibodies for CD70 and methods of manufacturing them.

[0231] Antibodies for CD70 are provided in this document.

[0232] In some embodiments, an antibody for CD70 of the description comprises any of the partial light chain sequences as listed in Table 1 and / or any of the partial heavy chain sequences as listed in Table 1. In Petition 870260028237, dated 03 / 25 / 2026, pp. 923 / 1082 103 / 230 Table 1, the underlined sequences are CDR sequences according to Kabat and those in bold according to Chothia.

[0233] Tables 2A-2B provide examples of sequences of CDR of the antibodies for CD70 provided in this document.

[0234] In some embodiments, the description provides an antibody (e.g., including antibody fragments, such as single-chain variable fragments (scFvs) that specifically bind to Cluster of Differentiation 70 (CD70), wherein the antibody comprises (a) a variable heavy chain (VH) region comprising (i) a complementarity-determining region (CDR1) VH comprising the sequence indicated in SEQ ID NO: 49, 50, 51, 55, 56, 57, 61, 62, 63, 67, 68, 69, 73, 74, 75, 79, 80, 81, 85, 86, 87, 91, 92, 93, 97, 98, 99, 103, 104, 105, 109, 110, 111, 115, 116, 117, 121, 122, 123, 127, 128, 129, 133, 134, 135, 139, 140, 141, 145, 146, 147, 151, 152, 153, 157, 158, 159, 163, 164, 165, 169, 170, 171, 175, 176, 177, 181, 182, 183, 187, 188, 189, 382, ​​383, 384, 388, 389, 390, 394, 395, 396, 400, 401, 402, 406, 407, 408, 412, 413, 414, 418, 419, 420, 424, 425, 426, 430, 431, 432, 663, 664, 665, 436, 437, 438, 442, 443, 444, 448, 449, 450, 454, 455, 456, 460, 461, 462, 466, 467, 468, 472, 473, 474, 478, 479, 480, 484, 485, 486, 490, 491, 492, 496, 497, 498, 502, 503, 504, 508, 509 or 510; (ii) a VH CDR2 comprising the sequence indicated in SEQ ID NO: 52, 53, 58, 59, 64, 65, 70, 71, 76, 77, 82, 83, 88, 89, 94, 95, 100, 101, 106, 107, 112, 113, 118, 119, 124, 125, 130, 131, 136, 137, 142, 143, 148, 149, 154, 155, 160, 161, 166, 167, 172, 173, 178, 179, 184, 185, 190, 191, 385, 386, 391, 392, 397, 398, 403, 404, 409, 410, 415, 416, 421, 422, 427, 428, 433, 434, 666, 667, 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 482, 487, 488, 493, 494, 499, 500, 505, 506, 511 or 512; and iii) a VH CDR3 comprising the sequence indicated in SEQ ID NO: 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 126, 132, 138, Petition 870260028237, dated 03 / 25 / 2026, pp. 924 / 1082 104 / 230 144, 150, 156, 162, 168, 174, 180, 186, 192, 387, 393, 399, 405, 411, 417, 423, 429, 435, 668, 441, 447, 453, 459, 465, 471, 477, 483, 489, 495, 501, 507 or 513; and / or a variable light chain (VL) region comprising (i) a CDR1 VL comprising the sequence indicated in SEQ ID NO: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226, 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262, 514, 517, 520, 523, 526, 529, 532, 535, 538, 669, 541, 544, 547, 550, 553, 556, 559, 562, 565, 568, 571, 574 or 577; (ii) a VL CDR2 comprising the sequence indicated in SEQ ID NO: 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245, 248, 251, 254, 257, 260, 263, 515, 518, 521, 524, 527, 530, 533, 536, 539, 670, 542, 545, 548, 551, 554, 557, 560, 563, 566, 569, 572, 575 or 578; and (iii) a VL CDR3 comprising the sequence indicated in SEQ ID NO: 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237, 240, 243, 246, 249, 252, 255, 258, 261, 264, 516, 519, 522, 525, 528, 531, 534, 537, 540, 671, 543, 546, 549, 552, 555, 558, 561, 564, 567, 570, 573, 576 or 579.

[0235] In some embodiments, the description provides an antibody (e.g., an scFv) that specifically binds to Cluster of Differentiation 70 (CD70), wherein the antibody comprises a variable heavy chain (VH) region comprising a VH CDR1, a VH CDR2, and a VH CDR3 of the VH sequence indicated in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381; and / or a variable light chain (VL) region comprising VL CDR1, VL CDR2 and VL CDR3 of the VL sequence indicated in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 661, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380. Petition 870260028237, dated 03 / 25 / 2026, pp. 925 / 1082 105 / 230

[0236] In some embodiments, the description provides an isolated antibody that binds specifically to CD70 and competes with any of the antibodies mentioned above.

[0237] In some embodiments, the present invention provides an antibody that binds to CD70 and competes with an antibody as described in this document, including 31H1, 63B2, 40E3, 42C3, 45F11, 64F9, 72C2, 2F10, 4F11, 10H10, 17G6, 65E11, P02B10, P07D03, P08A02, P08E02, P08F08, P08G02, P12B09, P12F02, P12G07, P13F04, P15D02, P16C05, 10A1, 10E2, 11A1, 11C1, 11D1, 11E1, 12A2, 12C4, 12C5, 12D3, 12D6, 12D7, 12F5, 12H4, 8C8, 8F7, 8F8, 9D8, 9E10, 9E5, 9F4 or 9F8.

[0238] In some embodiments, the invention also provides CDR portions of antibodies for CD70 antibodies based on CDR contact regions. CDR contact regions are regions of an antibody that imbue the antibody with specificity for an antigen. In general, CDR contact regions include residue positions in the CDR and Vernier zones that are constrained in order to maintain the loop structure suitable for the antibody to bind a specific antigen. See, for example, Makabe et al., J. Biol. Chem., 283:1156-1166, 2007. The determination of CDR contact regions is within the art.

[0239] The binding affinity (KD) of the CD70 antibody, as described in this document, to CD70 (such as human CD70 (e.g., (SEQ ID NO: 335)) can be from about 0.001 to about 5,000 nM. In some embodiments, the binding affinity is about 5,000 nM, 4,500 nM, 4,000 nM, 3,500 nM, 3,000 nM, 2,500 nM, 2,000 nM, 1,789 nM, 1,583 nM, 1,540 nM, 1,500 nM, 1,490 nM, 1,064 nM, 1,000 nM, 933 nM, 894 nM, 750 nM, 705 nM, 678 nM, 532 nM, 500 nM, 494 nM,400 nM, 349 nM, 340 nM, 353 nM, 300 nM, 250 nM, 244 nM, 231 nM, 225 nM, 207 nM, 200 nM, 186 nM, 172 nM, 136 nM, 113 nM, 104nM,101 Petition 870260028237, dated 03 / 25 / 2026, pp. 926 / 1082 106 / 230 nM, 100 nM, 90 nM, 83 nM, 79 nM, 74 nM, 54 nM, 50 nM, 45 nM, 42 nM, 40 nM, 35 nM, 32 nM, 30 nM, 25 nM, 24 nM, 22 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 12 nM, 10 nM, 9 nM, 8 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5.5 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.3 nM, 0.1 nM, 0.01 nM or 0.001 nM. In some embodiments, the binding affinity is less than about any one of 5000 nM, 4000 nM, 3000 nM, 2000 nM, 1000 nM, 900 nM, 800 nM, 250 nM, 200 nM, 100 nM, 50 nM, 30 nM, 20 nM, 10 nM, 7.5 nM, 7 nM, 6.5 nM, 6 nM, 5 nM, 4.5 nM, 4 nM, 3.5 nM, 3 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, or 0.5 nM.

[0240] In some embodiments, the description provides a nucleic acid that encodes any of the isolated antibodies mentioned above. In some embodiments, the description provides a vector comprising such nucleic acid. In some embodiments, the description provides a host cell comprising such nucleic acid.

[0241] The description further provides any of the antibodies mentioned above for use as a medicine. In some embodiments, the medicine is for use in the treatment of a CD70-related cancer selected from the group consisting of Renal Cell Carcinoma, Glioblastoma, glioma, such as low-grade glioma, Non-Hodgkin Lymphoma (NHL), Hodgkin's Disease (HD), Waldenstrom's macroglobulinemia, Acute Myeloid Leukemia, Multiple Myeloma, diffuse large cell lymphoma, follicular lymphoma or Non-Small Cell Lung Cancer.

[0242] In some embodiments, the description provides a method for treating a subject in need, comprising providing any of the antibodies mentioned above and administering said antibody to said subject.

[0243] In some forms, the description provides a com Petition 870260028237, dated 03 / 25 / 2026, pp. 927 / 1082 107 / 230 pharmaceutical position comprising any of the antibodies mentioned above.

[0244] In some embodiments, the description provides a method for treating a condition associated with malignant cells expressing CD70 in a subject comprising administering to a subject in need an effective amount of any of the antibodies mentioned above or a pharmaceutical composition comprising any of the antibodies mentioned above. In some embodiments, the condition is cancer. In some embodiments, the cancer is a CD70-related cancer selected from the group consisting of Renal Cell Carcinoma, Glioblastoma, glioma, such as low-grade glioma, Non-Hodgkin Lymphoma (NHL), Hodgkin's Disease (HD), Waldenstrom's macroglobulinemia, Acute Myeloid Leukemia, Multiple Myeloma, diffuse large cell lymphoma, follicular lymphoma, or Non-Small Cell Lung Cancer.

[0245] In some embodiments, the description provides a method for inhibiting tumor growth or progression in a subject possessing malignant cells expressing CD70 comprising administering to the subject in need an effective amount of the pharmaceutical composition of the description to the subject.

[0246] In some embodiments, the description provides a method of inhibiting metastasis of malignant cells expressing CD70 in a subject, comprising administering to the subject in need an effective amount of a pharmaceutical composition of the description to the subject.

[0247] In some embodiments, the description provides a method for inducing tumor regression in a subject possessing malignant cells expressing CD70 comprising administering to the subject in need an effective amount of the pharmaceutical composition of the description to the subject. Petition 870260028237, dated 03 / 25 / 2026, pp. 928 / 1082 108 / 230

[0248] In some embodiments, the antibody, comprising culturing the host cell of the description under conditions that result in the production of the antibody and isolating the antibody from the host cell or culture.

[0249] The antibodies useful in the present invention may include monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab')2, Fv, Fc, etc.), chimeric antibodies, bispecific antibodies, heteroconjugated antibodies, single-chain antibodies (ScFv), their mutants, fusion proteins comprising an antibody portion (e.g., a domain antibody), humanized antibodies, and any other modified configuration of the immunoglobulin molecule comprising an antigen recognition site of the required specificity, including antibody glycosylation variants, antibody amino acid sequence variants, and covalently modified antibodies. The antibodies may be murine, mouse, human, or of any other origin (including chimeric or humanized antibodies).

[0250] In some modalities, the monospecific antibody for CD70, as described in this document, is a monoclonal antibody. For example, the monospecific antibody CD70 is a human monoclonal antibody.

[0251] The description also provides the following illustrative options:

[0252] 1. An isolated antibody that binds specifically to Cluster of Differentiation 70 (CD70), wherein the antibody comprises (a) a variable heavy chain (VH) region comprising (i) a VH complementarity-determining region (CDR1) comprising the sequence indicated in SEQ ID NO: 49, 50, 51, 55, 56, 57, 61, 62, 63, 67, 68, 69, 73, 74, 75, 79, 80, 81, 85, 86, 87, 91, 92, 93, 97, 98, 99, 103, 104, 105, 109, 110, 111, 115, 116, 117, 121, Petition 870260028237, dated 03 / 25 / 2026, pp. 929 / 1082 109 / 230 122, 123, 127, 128, 129, 133, 134, 135, 139, 140, 141, 145, 146, 147, 151, 152, 153, 157, 158, 159, 163, 164, 165, 169, 170, 171, 175, 176, 177, 181, 182, 183, 187, 188, 189, 382, ​​383, 384, 388, 389, 390, 394, 395, 396, 400, 401, 402, 406, 407, 408, 412, 413, 414, 418, 419, 420, 424, 425, 426, 430, 431, 432, 663, 664, 665, 436, 437, 438, 442, 443, 444, 448, 449, 450, 454, 455, 456, 460, 461, 462, 466, 467, 468, 472, 473, 474, 478, 479, 480, 484, 485, 486, 490, 491, 492, 496, 497, 498, 502, 503, 504, 508, 509, or 510; (ii) a VH CDR2 comprising the sequence indicated in SEQ ID NO: 52, 53, 58, 59, 64, 65, 70, 71, 76, 77, 82, 83, 88, 89, 94, 95, 100, 101, 106, 107, 112, 113, 118, 119, 124, 125, 130, 131, 136, 137, 142, 143, 148, 149, 154, 155, 160, 161, 166, 167, 172, 173, 178, 179, 184, 185, 190, 191, 385, 386, 391, 392, 397, 398, 403, 404, 409, 410, 415, 416, 421, 422, 427, 428, 433, 434, 666, 667, 439, 440, 445, 446, 451, 452, 457, 458, 463, 464, 469, 470, 475, 476, 481, 482, 487, 488, 493, 494, 499, 500, 505, 506, 511 or 512; and iii) a VH CDR3 comprising the sequence indicated in SEQ ID NO: 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120,126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 387, 393, 399, 405, 411, 417, 423, 429, 435, 668, 441, 447, 453, 459, 465, 471, 477, 483, 489, 495, 501, 507 or 513; and / or (b) a variable light chain (VL) region comprising (i) a CDR1 VL comprising the sequence indicated in SEQ ID NO: 193, 196, 199, 202, 205, 208, 211, 214, 217, 220, 223, 226, 229, 232, 235, 238, 241, 244, 247, 250, 253, 256, 259, 262, 514, 517, 520, 523, 526, 529, 532, 535, 538, 669, 541, 544, 547, 550, 553, 556, 559, 562, 565, 568, 571, 574 or 577; (ii) a VL CDR2 comprising the sequence indicated in SEQ ID NO: 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 233, 236, 239, 242, 245, 248, 251, 254, 257, 260, 263, 515, 518, 521, 524, 527, 530, 533, 536, 539, 670, 542, 545, 548, 551, 554, 557, 560, 563, 566, 569, 572, 575 or 578; and (iii) Petition 870260028237, dated 03 / 25 / 2026, pp. 930 / 1082 110 / 230 a VL CDR3 comprising the sequence indicated in SEQ IDNO: 195, 198, 201, 204, 207, 210, 213, 216, 219, 222, 225, 228, 231, 234, 237, 240, 243, 246, 249, 252, 255, 258, 261, 264, 516, 519, 522, 525, 528, 531, 534, 537, 540, 671, 543, 546, 549, 552, 555, 558, 561, 564, 567, 570, 573, 576 or 579.

[0253] 2. An isolated antibody that binds specifically to Cluster of Differentiation 70 (CD70), where the antibody comprises: (a) a VH region comprising a VH CDR1, VH CDR2 and VH CDR3 of the VH sequence indicated in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 339, 341, 343, 345, 347, 349, 351, 353, 355, 662, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379 or 381; and / or (b) a VL region comprising VL CDR1, VL CDR2 and VL CDR3 of the VL sequence indicated in SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 338, 340, 342, 344, 346, 348, 350, 352, 354, 661, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378 or 380.

[0254] 3. An isolated antibody that binds specifically to CD70 and competes with the antibody according to modality 1.

[0255] 4. A nucleic acid that encodes the antibody of any of the forms from 1 to 3.

[0256] 5. A vector comprising nucleic acid of modality 4.

[0257] 6. A host cell comprising nucleic acid of modality 4.

[0258] 7. The antibody of any of the embodiments from 1 to 3, for use as a medicine.

[0259] 8. The antibody of modality 7, wherein the drug is for use in the treatment of a CD70-related cancer selected from the group consisting of Renal Cell Carcinoma, Glioblastoma, Petition 870260028237, dated 03 / 25 / 2026, pp. 931 / 1082 111 / 230 glioma, such as low-grade glioma, Non-Hodgkin Lymphoma (NHL), Hodgkin's Disease (HD), Waldenstrom's macroglobulinemia, Acute Myeloid Leukemia, Multiple Myeloma, diffuse large cell lymphoma, follicular lymphoma, or Non-Small Cell Lung Cancer.

[0260] 9. A method for treating a person in need comprising: a. provide the antibody according to any of the modalities from 1 to 3; and b. administer the aforementioned antibody to the aforementioned subject.

[0261] 10. A pharmaceutical composition comprising the antibody of any of the embodiments from 1 to 3.

[0262] 11. A method for treating a condition associated with malignant cells expressing CD70 in a subject comprising administering to a subject in need an effective amount of the antibody of any of the embodiments 1 to 3 or of the pharmaceutical composition of embodiment 10.

[0263] 12. The method of modality 11, in which the condition is cancer.

[0264] 13. The modality 12 method, wherein the cancer is a CD70-related cancer selected from the group consisting of Renal Cell Carcinoma, Glioblastoma, glioma, such as low-grade glioma, Non-Hodgkin Lymphoma (NHL), Hodgkin's Disease (HD), Waldenstrom's Macroglobulinemia, Acute Myeloid Leukemia, Multiple Myeloma, diffuse large cell lymphoma, follicular lymphoma or Non-Small Cell Lung Cancer.

[0265] 14. A method for inhibiting tumor growth or progression in a subject possessing malignant cells expressing CD70, comprising administering to the subject in need an effective amount of the pharmaceutical composition of embodiment 10 to the subject. Petition 870260028237, dated 03 / 25 / 2026, pp. 932 / 1082 112 / 230

[0266] 15. Method for inhibiting metastasis of malignant cells expressing CD70 in a subject, comprising administering to the subject in need an effective amount of the pharmaceutical composition of embodiment 10 to the subject.

[0267] 16. A method for inducing tumor regression in a subject possessing malignant cells expressing CD70, comprising administering to the subject in need an effective amount of the pharmaceutical composition of modality 10 to the subject.

[0268] 17. Method for producing an antibody, comprising culturing the host cell of embodiment 6 under conditions that result in the production of the antibody and isolating the antibody from the host cell or culture. METHOD OF MANIPULATING AN IMMUNE CELL

[0269] Methods for preparing immune cells for use in immunotherapy are provided in this document. In some embodiments, the methods comprise introducing a CAR as described into immune cells and expanding the cells. In some embodiments, the description relates to a method of manipulating an immune cell comprising: providing an immune cell and expressing on the cell surface at least one CAR, as described in this document. Methods for manipulating immune cells are described, for example, in PCT Patent Application Publication No. WO / 2014 / 039523, WO / 2014 / 184741, WO / 2014 / 191128, WO / 2014 / 184744 and WO / 2014 / 184143, each of which is incorporated herein by reference in its entirety. In some embodiments, the method comprises: transfecting the cell with at least one polynucleotide encoding CAR as described above and expressing the polynucleotides in the cell.

[0270] In some embodiments, polynucleotides are present in lentiviral vectors for stable expression in cells. Petition 870260028237, dated 03 / 25 / 2026, pp. 933 / 1082 113 / 230

[0271] In some embodiments, the method may further comprise a step to genetically modify a cell by disrupting or inactivating at least one gene it expresses, for example, without limitation, a component of the TCR, a target for an immunosuppressive agent, an HLA gene, CD70 and / or an immune checkpoint protein, such as, for example, PDCD1 or CTLA-4. By disrupting or inactivating a gene, the aim is that the gene of interest is not expressed in a functional protein form. In some embodiments, the gene to be disrupted or inactivated is selected from the group consisting of, for example, without limitation, TCRa, TCRe, CD52, GR, PD-1, CD70 and CTLA-4. In some embodiments, the method comprises disrupting or inactivating one or more genes by introducing into the cells a rare-cleaving endonuclease capable of selectively inactivating a gene by selective DNA cleavage.In some embodiments, the rare cleavage endonuclease may be, for example, a zinc finger nuclease (ZFN), megaTAL nuclease, meganuclease, transcription activator-type effector nuclease (TALE-nuclease), or CRISPR-associated endonuclease.

[0272] In some embodiments, an additional catalytic domain is used with a rare-cutting endonuclease to increase its ability to inactivate targeted genes. For example, an additional catalytic domain may be a DNA end-processing enzyme. Non-limiting examples of DNA end-processing enzymes include 5-3' exonucleases, 3-5' exonucleases, 5-3' alkaline exonucleases, 5' flap endonucleases, helicases, phosphatases, hydrolases, and template-independent DNA polymerases. Non-limiting examples of such a catalytic domain are composed of a protein domain or a catalytically active derivative of the protein domain selected from the group consisting of hExoI (EXO1_HUMAN), Yeast Exol (EXO1_YEAST), E. coli Exol, Human TREX2, Camun TREX1 Petition 870260028237, dated 03 / 25 / 2026, pp. 934 / 1082 114 / 230 dongo, Human TREX1, Bovine TREX1, Rat TREX1, TdT (terminal deoxynucleotidyl transferase) Human DNA2, Yeast DNA2 (DNA2_YEAST). In some embodiments, an additional catalytic domain may have 3'-5'-exonuclease activity and, in some embodiments, said additional catalytic domain is TREX, such as a TREX2 catalytic domain (WO2012 / 058458). In some embodiments, said catalytic domain is encoded by a single-stranded TREX polypeptide. The additional catalytic domain may be fused to a fusion protein or chimeric nuclease protein. In some embodiments, the additional catalytic domain is fused using, for example, a peptide linker.

[0273] In some embodiments, the method further comprises a step of introducing into cells an exogenous nucleic acid comprising at least one sequence homologous to a portion of the target nucleic acid sequence, such that homologous recombination occurs between the target nucleic acid sequence and the exogenous nucleic acid. In some embodiments, said exogenous nucleic acid comprises a first and a second portion that are homologous to the 5' and 3' regions of the target nucleic acid sequence, respectively. The exogenous nucleic acid may also comprise a third portion positioned between the first and second portions that does not comprise any homology with the 5' and 3' regions of the target nucleic acid sequence. After cleavage of the target nucleic acid sequence, a homologous recombination event is stimulated between the target nucleic acid sequence and the exogenous nucleic acid.In some embodiments, homologous sequences of at least about 50 bp, greater than about 100 bp, or greater than about 200 bp can be used within the donor matrix. The exogenous nucleic acid can have, for example, without limitation, about 200 bp to about 6,000 bp, or about 1,000 bp to about 2,000 bp. Petition 870260028237, dated 03 / 25 / 2026, pp. 935 / 1082 115 / 230 bp. The shared nucleic acid homologies are located in regions flanking upstream and downstream of the break site, and the nucleic acid sequence to be introduced is located between the two arms.

[0274] In some embodiments, a nucleic acid successively comprises a first homology region with sequences upstream of said cleavage; a sequence to inactivate a targeted gene selected from the group consisting of TCRa, TCRe, CD52, CD70, glucocorticoid receptor (GR), deoxytitidine kinase (DCK), and an immune checkpoint protein such as, for example, programmed death-1 (PD-1); and a second homology region with sequences downstream of the cleavage. The polynucleotide introduction step may be simultaneous, before, or after the introduction or expression of the rare-cleavage endonuclease. Depending on the location of the target nucleic acid sequence where the disruption event occurred, such exogenous nucleic acid may be used to knock out a gene, for example, when the exogenous nucleic acid is located within the gene's open reading frame, or to introduce new sequences or genes of interest.Sequence insertions using such exogenous nucleic acid can be used to modify a targeted existing gene by correcting or replacing the gene (allele switching as a non-limiting example), or to negatively or positively regulate the expression of the targeted gene (promoter switching as a non-limiting example), correcting or replacing the targeted gene. In some embodiments, the inactivation of a selected gene from the group consisting of TCRa, TCRe, CD52, CD70, GR, DCK, and immune checkpoint proteins can be done at a precise genomic location targeted by a specific TALE-nuclease, wherein said specific TALE-nuclease catalyzes a cleavage and wherein the exogenous nucleic acid comprising successively... Petition 870260028237, dated 03 / 25 / 2026, pp. 936 / 1082 116 / 230 at least one homology region and a sequence to inactivate a selected targeted gene from the group consisting of TCRa, TCRe, CD52, CD70, GR, DCK, immune checkpoint proteins, which is integrated by homologous recombination. In some embodiments, several genes can be disrupted or inactivated, successively or simultaneously, using multiple TALE-nucleases, targeting, respectively and specifically, a defined gene and several specific polynucleotides for specific gene inactivation.

[0275] In some embodiments, the method comprises inactivation of one or more additional genes selected from the group consisting of TCRα, TCRβ, CD52, CD70, GR, DCK, and immune checkpoint proteins. In some embodiments, gene inactivation may be accomplished by introducing into cells at least one rare-cutting endonuclease such that the rare-cutting endonuclease specifically catalyzes cleavage at a targeted sequence of the cellular genome; and, optionally, by introducing into cells an exogenous nucleic acid comprising successively a first homology region with sequences upstream of the cleavage, a sequence to be inserted into the cellular genome, and a second homology region with sequences downstream of the cleavage; wherein the introduced exogenous nucleic acid inactivates a gene and integrates at least one exogenous polynucleotide sequence encoding at least one recombinant protein of interest.In some forms, the exogenous polynucleotide sequence is integrated within a gene that encodes a protein selected from the group consisting of TCRα, TCRβ, CD52, CD70, GR, DCK, and immune checkpoint protein.

[0276] In another aspect, a step in genetic modification of cells may comprise: modifying T cells by disrupting or inactivating at least one gene that expresses a target for an immunosuppressive agent; and expanding the cells, optionally in the presence of Petition 870260028237, dated 03 / 25 / 2026, pp. 937 / 1082 117 / 230 Immunosuppressive agent. An immunosuppressive agent is an agent that suppresses immune function by one of several mechanisms of action. An immunosuppressive agent may decrease the extent and / or voracity of an immune response. Non-limiting examples of immunosuppressive agents include calcineurin inhibitors, rapamycin targets, interleukin-2 α-chain blockers, inosine monophosphate dehydrogenase inhibitors, dihydrofolic acid reductase inhibitors, corticosteroids, and immunosuppressive antimetabolites. Some cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act by activating T cells or by inhibiting the activation of helper cells. The methods described allow for the conferral of immunosuppressive resistance to T cells for immunotherapy by disrupting or inactivating the target of the immunosuppressive agent in T cells.As non-limiting examples, targets for the immunosuppressive agent may be a receptor for an immunosuppressive agent, such as, for example, but not limited to, CD52, glucocorticoid receptor (GR), members of the FKBP gene family, and members of the cyclophilin gene family.

[0277] In some embodiments, the genetic modification of the method involves the expression, in cells supplied for manipulation, of a rare-cutting endonuclease such that the rare-cutting endonuclease specifically catalyzes cleavage in a targeted gene, thereby disrupting or inactivating the targeted gene. In some embodiments, a method for manipulating cells comprises at least one of the following steps: supplying a T cell, such as from a cell culture or a blood sample; selecting a gene in the T cell that expresses a target for an immunosuppressive agent; introducing into the T cell a rare-cutting endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) the gene encoding a target for the immunosuppressive agent. Petition 870260028237, dated 03 / 25 / 2026, pp. 938 / 1082 118 / 230 immunosuppressive agent and expand the cells, optionally, in the presence of the immunosuppressive agent.

[0278] In some embodiments, the method comprises: providing a T cell, such as from a cell culture or a blood sample; selecting a gene on the T cell in which the gene expresses a target for an immunosuppressive agent; transfecting the T cell with nucleic acid encoding a rare-cut endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) the gene encoding a target for the immunosuppressive agent and expressing the rare-cut endonucleases on the T cells; and optionally expanding the cells in the presence of the immunosuppressive agent.

[0279] In some embodiments, the rare-cut endonuclease specifically targets CD52 or GR. In some embodiments, the gene selected for inactivation encodes CD52, and the immunosuppressive treatment comprises a humanized antibody that targets the CD52 antigen. In some embodiments, the gene selected for inactivation encodes GR, and the immunosuppressive treatment comprises a corticosteroid such as dexamethasone. In some embodiments, the gene selected for inactivation is a member of the FKBP gene family or a variant thereof, and the immunosuppressive treatment comprises FK506, also known as tacrolimus or fujimicin. In some embodiments, the member of the FKBP gene family is FKBP12 or a variant thereof. In some embodiments, the gene selected for inactivation is a member of the cyclophilin gene family or a variant thereof, and the immunosuppressive treatment comprises cyclosporine.

[0280] In some embodiments, the rare-cut endonuclease may be, for example, a zinc finger nuclease (ZFN), megaTAL nuclease, meganuclease, or a transcription activator-type effector nuclease. Petition 870260028237, dated 03 / 25 / 2026, pp. 939 / 1082 119 / 230 tion (TALE-nuclease), or CRISPR-associated endonuclease. In some embodiments, the rare-cutting endonuclease is a TALEnuclease. In some embodiments, the rare-cutting nuclease is a CRISPR nuclease, with a guide RNA at least partially complementary or fully complementary to a target site.

[0281] Generally, a CRISPR-associated nuclease is provided with a guide RNA (gRNA) or the functional equivalent. The gRNA is composed of two parts; a crispr-RNA (crRNA) that is specific for a target genomic DNA sequence and a trans-activating RNA (tracrRNA) that facilitates the binding of Cas to DNA. In some embodiments, crRNA and tracrRNA may be present on the same RNA oligonucleotide, referred to as a single guide RNA (sgRNA). In some embodiments, crRNA and tracrRNA may be present as separate RNA oligonucleotides. As used in this document, the term guide RNA or gRNA refers to the combination of a tracrRNA and a crRNA, present as an sgRNA or a crRNA:tracrRNA duplex. In some embodiments, the CRISPR-associated nuclease is a Cas9 nuclease. In some embodiments, the Cas9 protein may be derived from Streptococcus pyogenes (SpCas9).In some embodiments, the Cas9 protein can be derived from other strains of bacteria, including Staphylococcus aureus (Sacas9). In some embodiments, the Cas endonuclease is selected from the group comprising SpCas9, SpCas9-HF1, SpCas9-HF2, SpCas9-HF3, SpCas9-HF4, SaCas9, FnCpf, FnCas9, eSpCas9, C2C1, C2C3, Cpf1, Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csnl and Csx12), Cas10, Csyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Nsxl7, Nsxl4, Nsx10, Nsx16, NsaX, Nsx3, Nsxl, Nsxl5, Nsfl, Nsf2, Nsf3 or Nsf4.

[0282] Studies suggest that adoptive T cell transfer Petition 870260028237, dated 03 / 25 / 2026, pp. 940 / 1082 120 / 230 derived from less differentiated subsets (i.e., Tscm or Tcm) leads to prolonged persistence in vivo (see, for example, Berger, C. et al., The Journal of Clinical Investigation, 118(1): 294-305 (2008)). Thus, genetic knockdown of CD70 in the CAR T product is an important consideration to prevent T cell differentiation.

[0283] In some embodiments, the genetic modification of the method involves the expression, in cells supplied for manipulation, of a rare-cutting endonuclease such that the rare-cutting endonuclease specifically catalyzes cleavage in the CD70 gene, thereby disrupting or inactivating the CD70 gene. In some embodiments, a method for manipulating cells comprises at least one of the following steps: supplying a T cell, such as from a cell culture or a blood sample; introducing into the T cell a rare-cutting endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) the gene encoding CD70; and expanding the cells.

[0284] In some embodiments, the method comprises: providing a T cell, such as from a cell culture or a blood sample; transfecting the T cell with nucleic acid encoding a rare-cut endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) the gene encoding CD70 and expressing rare-cut endonucleases in T cells; and expanding the cells.

[0285] In some embodiments, the rare-cutting endonuclease may be, for example, a meganuclease, a zinc finger nuclease, or a TALE-nuclease (TALEN). In some embodiments, the rare-cutting endonuclease is a TALE-nuclease. In some embodiments, the rare-cutting nuclease is a CRISPR-associated nuclease, with a guide RNA that is at least partially complementary or fully complementary to a target site. Petition 870260028237, dated 03 / 25 / 2026, pp. 941 / 1082 121 / 230

[0286] Methods for manipulating T cells suitable for immunotherapy are also provided in this document, wherein the methods comprise: genetically modifying T cells by disrupting or inactivating at least one immune checkpoint protein. In some embodiments, the immune checkpoint protein is, for example, PD-1 and / or CTLA-4. In some embodiments, methods for genetically modifying a cell comprise: modifying T cells by disrupting or inactivating at least one immune checkpoint protein; and expanding the cells. Immune checkpoint proteins include, among others, Programmed Death 1 (PD-1, also known as PDCD1 or CD279, accession number: NM—005018), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4, also known as CD152, GenBank accession number AF414120.1), LAG3 (also known as CD223, accession number: NM—002286.5), Tim3 (also known as HAVCR2, GenBank accession number: JX049979).1), BTLA (also known as CD272, accession number: NM—181780.3), BY55 (also known as CD160, GenBank accession number: CR541888.1), TIGIT (also known as VSTM3, accession number: NM—173799), B7H5 (also known as C10orf54, mouse vista gene homolog, accession number: NM—022153.1), LAIR1 (also known as CD305, GenBank accession number: CR542051.1), SIGLEC10 (GeneBank accession number: AY358337.1), 2B4 (also known as CD244, accession number: NM—001166664.1), which directly inhibits immune cells. For example, CTLA-4 is a cell surface protein expressed on certain CD4 and CD8 T cells; When bound by their ligands (B7-1 and B7-2) to antigen-presenting cells, T cell activation and effector function are inhibited.

[0287] In some modalities, the aforementioned method for manipulating cells comprises at least one of the following steps: provide Petition 870260028237, dated 03 / 25 / 2026, page 942 / 1082 122 / 230 to provide a T cell, such as from a cell culture or a blood sample; to introduce into the T cell a rare-cut endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) a gene encoding an immune checkpoint protein; and to expand the cells. In some embodiments, the method comprises: providing a T cell, such as from a cell culture or a blood sample; transfecting said T cell with nucleic acid encoding a rare-cut endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) a gene encoding an immune checkpoint protein and expressing the rare-cut endonucleases in the T cells; and expanding the cells.In some embodiments, the rare-cutting endonuclease specifically targets a selected gene from the cluster consisting of: PD-1, CTLA-4, LAG3, Tim3, BTLA, BY55, TIGIT, B7H5, LAIR1, SIGLEC10, 2B4, TCRa, and TCRe. In some embodiments, the rare-cutting endonuclease may be a meganuclease, a zinc finger nuclease, or a TALE-nuclease. In some embodiments, the rare-cutting endonuclease is a TALE-nuclease. In some embodiments, the rare-cutting nuclease is a Cas9 nuclease, with a guide RNA that is at least partially or fully complementary to a target site.

[0288] In some embodiments, the present description may be particularly suitable for allogeneic immunotherapy. In such embodiments, cells may be modified by a method comprising: disrupting or inactivating at least one gene encoding a component of the T cell receptor (TCR) in T cells; and expanding the T cells. In some embodiments, the genetic modification of the method is based on the expression, in cells provided for manipulation, of a rare-cutting endonuclease such that the endonuclease of Petition 870260028237, dated 03 / 25 / 2026, pp. 943 / 1082 123 / 230 rare cut specifically catalyzes cleavage in a targeted gene, thereby disrupting or inactivating the targeted gene. In some embodiments, the said method for manipulating cells comprises at least one of the following steps: providing a T cell, such as from a cell culture or a blood sample; introducing into the T cell a rare cut endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) at least one gene encoding a component of the T cell receptor (TCR); and expanding the cells.

[0289] In some embodiments, the method comprises: providing a T cell, such as from a cell culture or a blood sample; transfecting said T cell with nucleic acid encoding a rare-cut endonuclease capable of selectively inactivating by DNA cleavage (in some embodiments by double-strand breaks) at least one gene encoding a component of the T cell receptor (TCR); expressing the rare-cut endonucleases on the T cells; separating the transformed T cells, which do not express TCR on their cell surface; and expanding the cells.

[0290] In some embodiments, the rare-cutting endonuclease may be a meganuclease, a zinc finger nuclease, or a TALE-nuclease. In some embodiments, the rare-cutting endonuclease is a TALE-nuclease. In some embodiments, TALEnucleases recognize and cleave a sequence encoding TCRa or TCRe. In some embodiments, a TALE-nuclease comprises a polypeptide sequence selected from the amino acid sequence indicated in SEQ ID NO: 281, 282, 283, 284, 285, 286, 287, 288, 289, or 290. TALE-nuclease polypeptide sequences: Repeat TRAC T01-L Petition 870260028237, dated 03 / 25 / 2026, page 944 / 1082 124 / 230 NNGGKQALETVQRLLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLC QAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTPEQVVAIASNIGG KQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLPVLCQAHG LTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTQQVVAIASNGGGRPALE (SEQ ID NO: 281). Repeat TRAC T01-R LTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLC QAHGLTPQQVVAIASNNGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLPVLCQAHGLTQVVAIASNNGGKQALETVQRLLP VLCQAHGLTQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNIGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQ RLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVVQAHGLTQVVAIASNNGGQALETVQRLLPVLCQAHGLTQQVVAIASNGGGRPALE (SEQ ID NO: 282). Repeat TRBC T01-L LTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASPetição 870260028237, dated 25 / 03 / 2026, p. 945 / 1082 125 / 230 NGGGKQALETVQRLLPVLCQAHGLTQQVVAIASNNGGKQALETVQRLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLPVLC QAHGLTPQQVVAIASNGGGKQALETVQRLPVLCQAHGLTQQVVAIASNNGGKQALETVQRLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTQQVVAIASNNGG KQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHG LTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTQQVVAIASNGGGRPALE (SEQ ID NO: 283). Repeat TRBC T01-R NPQRSTVWYLTPQVVAIASNNGGQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGQALETVQRLPVLCQAHGLTPQVVAIASNNGGQALETVQRLLPVLCQAHGLTQQVVAIASNNGGKQALETVQ RLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTQVVAIASNGGGQALETVQRLPVLCQAHGLTQQVVAIASNGGGKQALETV QRLLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLPVLCQAHGLTPQVVAIASNGGGKQALETVQRLPVLCQAHGLTQQVVAIASNNGKQALETVQRLLPVLCQAHGLTQQVVAIASNNGGKQALE VQRLPVLCQAHGLTQQVVAIASNNGGKQALETVQRLPVLCQAHGLTPQVVAIASNGGGQALETVQRLPVLCQAHGLTQQVVAIASNNGGQALETVQRLLPVLCQAHGLTQQVVAIASNNGGGRPALE (SEQ ID NO: 284). Repeat TRBC T02-L Petition 870260028237, dated 3 / 25 / 2026, p. 946 / 1082 126 / 230 LTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPV VLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGRPALE (SEQ ID NO: 285). Repeat TRBC T02-R LTPQQVVAIASNNGGQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGQALETVQRLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLC QAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLP VLCQAHGLTQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTQVVAIASNGGGQALETVQRLPVLCQAHGLTQQVVAIASNNGGKQALETVQ RLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVIAASNGGGQALETVQRLPVLCQAHGLTQQVVAIASngGGQALETVQRLLPVLCQAHGLTQQVVAIASNGGGRPALE (SEQ ID NO: 286). Petition 870260028237, dated 3 / 25 / 2026, p. 947 / 1082 127 / 230 Repeat CD52 T02-L LTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHD (SEQ ID NO: 287). Repeat CD52 T02-R LTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLC QAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLP VLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLPVLCQAHGLTQVVAIASNGGGKQALETVQRLPVLCQAHGLTQVVAIASNNGGQALETVQ RLLPVLCQAHGLTQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHLTPQQVVAIASNGGGRPALE (SEQ ID NO: 288). Petition 870260028237, dated 3 / 25 / 2026, p. 948 / 1082 128 / 230 Repeat CD70-L LTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNG VLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQVVAIASNGGGKQALETVQRLLPVLCQAHGLTPQVVAIASNIGGKQALETVQRLLPVLCQAHGLTPQVVAIASNIGGKQALETVQRLLPVLCQAHGLTPQVVAIASNGGGRPALE (SEQ ID NO: 289) Repeat CD70-R LTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPQQVVAIASNGGGQALETVQRLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLPVLCQAHGLTPQQVVAIAASngGGKQALETVQRLLPVLC QAHGLTQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNGGGKQALETVQRLPVLCQAHGLTQQVVAIASngGGKQALETVQRLLP VLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTPEQVVAIASNIGGKQALETVQALLPVLCQAHGLTPQQVVAIASNNGGKQALETVQRLLPVLCQAHGLTPEQVVAIASHDGGKQALETVQ RLLPVLCQAHGLTQQVVAIASNGGGQALETVQRLPVLCQAHGLTQQVVAIASNNGGQALETVQRLPVLCQAHGLTPEQVVAIASHDGGKQALETVQRLLPVLCQAHGLTQQVVAIASNGGGRPALE (SEQ ID NO: 290) Petition 870260028237, dated 3 / 25 / 2026, p. 949 / 1082 129 / 230

[0291] In another aspect, another step in genetic modification of the cell may be a method for expanding TCRa-deficient T cells comprising introducing pTa (also known as preTCRa) or a functional variant thereof into the T cell and expanding the cells, optionally by stimulation of the CD3 complex. In some embodiments, the method comprises: a) transfecting the cells with nucleic acid encoding at least one pTα fragment to support CD3 surface expression; b) expressing said pTα in the cells; and c) expanding the cells, optionally by stimulation of the CD3 complex.

[0292] Methods are also provided for preparing T cells for immunotherapy comprising steps of the method for expansion into T cells. In some embodiments, the pTα polynucleotide sequence can be introduced randomly or by homologous recombination. In some embodiments, the insertion can be associated with inactivation of the TCRα gene.

[0293] Different functional variants of pTα can be used. A functional variant of the peptide refers to a molecule substantially similar to the entire peptide or a fragment thereof. A pTα fragment or functional variant thereof refers to any subset of the molecule, i.e., a peptide shorter than the full-length pTα. In some embodiments, pTα or functional variants may be, for example, full-length pTα or a C-terminal truncated version of pTα. The C-terminal truncated pTα lacks one or more residues at the C-terminal end. As non-limiting examples, the C-terminal truncated version of pTα lacks 18, 48, 62, 78, 92, 110, or 114 residues from the C-terminal end of the protein. Variants in the amino acid sequence of the peptide may be prepared by mutations in the DNA encoding the peptide. Such functional variants include, for example, deletions, insertions or substitutions. Petition 870260028237, dated 03 / 25 / 2026, page 950 / 1082 130 / 230 residue mutations within the amino acid sequence. Any combination of deletion, insertion, and substitution can also be made to arrive at the final construct, provided that the final construct possesses the desired activity, in particular the restoration of a functional CD3 complex. In some embodiments, at least one mutation is introduced into different pTa versions as described above to affect dimerization. As a non-limiting example, the mutant residue may be at least W46R, D22A, K24A, R102A, or R117A of the human pTa protein or aligned positions using the CLUSTALW method in the pTα family or homologous member. In some embodiments, pTα or a variant thereof as described above comprises the mutant residue W46R or the mutant residues D22A, K24A, R102A, and R117A. In some embodiments, the aforementioned pTα or variants are also fused to a signal transducer domain such as CD28, OX40, ICOS, CD27, CD137 (4-1BB) and CD8 as non-limiting examples.The extracellular domain of pTα or variants as described above can be fused to a fragment of the TCRα protein, particularly the transmembrane and intracellular domains of TCRα. pTα variants can also be fused to the intracellular domain of TCRα.

[0294] In some embodiments, pTα versions can be fused to an extracellular ligand-binding domain. In some embodiments, pTα or a functional variant thereof is fused to a single-chain antibody fragment (scFv) comprising the heavy and light variable fragment of a target antigen-specific monoclonal antibody linked by a flexible peptide linker.

[0295] The term TCRα-deficient T cell refers to an isolated T cell that is devoid of expression of a functional TCRα chain. This can be achieved by different means, including but not limited to, manipulating a T cell so that it does not express any functional TCRα on its cell surface or Petition 870260028237, dated 03 / 25 / 2026, pp. 951 / 1082 131 / 230 by manipulating a T cell so that it produces a very small functional TCRa chain on its surface or by manipulating a T cell to express the mutant or truncated form of the TCRa chain. TCRa-deficient cells can no longer be expanded by the CD3 complex. Thus, to overcome this problem and allow the proliferation of TCRα-deficient cells, pTa or its functional variant is introduced into the cells, thereby restoring a functional CD3 complex. In some embodiments, the method further comprises introducing into said T cells rare-cutting endonucleases capable of selectively inactivating by DNA cleavage a gene encoding a component of the T cell receptor (TCR). In some embodiments, the rare-cutting endonuclease is a TALEnuclease.

[0296] In another aspect, the engineered T cells obtained by the methods described in this document can come into contact with bispecific antibodies. For example, T cells can come into contact with bispecific antibodies ex vivo before administration to a patient, or in vivo after administration to a patient. Bispecific antibodies comprise two variable regions with properties distinct from the antigen that facilitate placing the engineered cells close to a target antigen. As a non-limiting example, a bispecific antibody can be directed against a tumor marker and lymphocyte antigen, such as, for example, but not limited to, CD3, and has the potential to redirect and activate any circulating T cells against tumors.

[0297] In some embodiments, the polynucleotides encoding polypeptides according to the present description may be mRNA that is introduced directly into cells, for example, by electroporation. In some embodiments, cytoPulse technology may be used to transiently permeabilize living cells to the Petition 870260028237, dated 03 / 25 / 2026, pages 952 / 1082 132 / 230 distribution of material in cells. The parameters can be modified to determine the conditions for high-efficiency transfection with minimal mortality.

[0298] Also provided in this document are methods for transfecting T cells. In some embodiments, the method comprises: placing a T cell in contact with RNA and applying to the T cell an agile pulse sequence consisting of: (a) an electrical pulse with a voltage variation of about 2250 to 3000 V per centimeter; (b) a pulse width of 0.1 ms; (c) a pulse interval of about 0.2 ms to about 10 ms between the electrical pulses of step (a) and (b); (d) an electrical pulse with a voltage variation of about 2250 to 3000 V with a pulse width of about 100 ms and a pulse interval of about 100 ms between the electrical pulse of step (b) and the first electrical pulse of step (c); and (e) four electrical pulses, with a voltage of about 325 V with a pulse width of about 0.2 ms and a pulse interval of 2 ms between each of the 4 electrical pulses.In some embodiments, a method for transfecting a T cell comprising bringing said cell into contact with RNA and applying to the T cell an agile pulse sequence comprising: (a) an electrical pulse with a voltage of about 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2400, 2450, 2500, 2600, 2700, 2800, 2900 or 3000 V per centimeter; (b) a pulse width of 0.1 ms; (c) and a pulse interval of about 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ms between the electrical pulses of step (a) and (b); (d) an electrical pulse with a voltage variation of approximately 2250, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2400, 2450, 2500, 2600, 2700, 2800, 2900 or 3000V with a pulse width of 100 ms and a pulse interval of 100 ms between the electrical pulse of step (b) and the first electrical pulse of step (c); and (e) 4 electrical pulses with a voltage of approximately 325 V with a pulse width of approximately 0.2 ms and an interval of. Petition 870260028237, dated 03 / 25 / 2026, pp. 953 / 1082 133 / 230 pulse of approximately 2 ms between each of the 4 electrical pulses. Any values ​​included in the value range described above are disclosed in this application. The electroporation medium may be any suitable medium known in the art, such as BTXpress Cytoporation®Media T4, made available by BTX. In some embodiments, the electroporation medium has conductivity in a range spanning from about 0.01 to about 1.0 milliSiemens.

[0299] In some embodiments, as non-limiting examples, an RNA encodes a rare-cut endonuclease, a rare-cut endonuclease monomer such as semi-TALE-nuclease, a CAR, at least one component of the multi-stranded chimeric antigen receptor, a pTa or functional variant thereof, an exogenous nucleic acid and / or an additional catalytic domain. MANIPULATED IMMUNE CELLS

[0300] The invention also provides engineered immune cells comprising any of the CAR polynucleotides described in this document. In some embodiments, a CAR can be introduced into an immune cell as a transgene via a plasmid vector. In some embodiments, the plasmid vector may also contain, for example, a selection marker that provides identification and / or selection of cells that have received the vector.

[0301] CAR polypeptides can be synthesized in situ in the cell after the introduction of polynucleotides encoding CAR polypeptides into the cell. Alternatively, CAR polypeptides can be produced outside the cells and then introduced into the cells. Methods for introducing a polynucleotide construct into cells are known in the art. In some embodiments, stable transformation methods can be used to integrate the polynucleotide construct into the cell genome. In other embodiments, transient transformation methods can be used to express transient Petition 870260028237, dated 03 / 25 / 2026, pp. 954 / 1082 134 / 230 specifically the polynucleotide construct and the polynucleotide construct not integrated into the cell genome. In other embodiments, virus-mediated methods may be used. Polynucleotides can be introduced into a cell by any suitable means, such as, for example, recombinant viral vectors (e.g., retroviruses, adenoviruses), liposomes, and the like. Transient transformation methods include, for example, but not limited to, microinjection, electroporation, or particle bombardment. Polynucleotides can be incorporated into vectors, such as, for example, plasmid vectors or viral vectors.

[0302] Isolated cells and cell lines obtained by the cell manipulation methods described above and provided in this document are also provided. In some embodiments, an isolated cell comprises at least one CAR as described above. In some embodiments, an isolated cell comprises a population of CARs, each CAR comprising different extracellular ligand-binding domains.

[0303] Isolated immune cells obtained according to any of the methods described above are also provided in this document. Any immune cell capable of expressing heterologous DNAs can be used for the purpose of expressing the CAR of interest. In some embodiments, the immune cell is a T cell. In some embodiments, an immune cell can be derived, for example, without limitation, from a stem cell. Stem cells can be adult stem cells, non-human embryonic stem cells, more particularly non-human stem cells, umbilical cord blood stem cells, progenitor cells, bone marrow stem cells, induced pluripotent stem cells, totipotent stem cells, or hematopoietic stem cells. Representative human cells are CD34+ cells. The isolated cell can also be a cell Petition 870260028237, dated 03 / 25 / 2026, pages 955 / 1082 135 / 230 dendritic cell, killer dendritic cell, mast cell, an NK cell, a B cell, or a T cell selected from the group consisting of inflammatory T lymphocytes, cytotoxic T lymphocytes, regulatory T lymphocytes, or helper T lymphocytes. In some embodiments, the cell may be derived from the group consisting of CD4+ T lymphocytes and CD8+ T lymphocytes.

[0304] In some embodiments, the engineered immune cells that express on their cell surface membrane a specific CAR for CD70 of the description comprise a percentage of stem cell memory and core memory cells greater than 10%, 20%, 30%, 40%, 50%, or 60%. In some embodiments, the engineered immune cells that express on their cell surface membrane a specific CAR for CD70 of the description comprise a percentage of stem cell memory and core memory cells of about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 15% to about 50%, about 15% to about 40%, about 20% to about 60%, or about 20% to about 70%.

[0305] In some embodiments, the immune cell is an inflammatory T lymphocyte that expresses any of the CARs described in this document. In some embodiments, the immune cell is a cytotoxic T lymphocyte that expresses any of the CARs described in this document. In some embodiments, the immune cell is a regulatory T lymphocyte that expresses any of the CARs described in this document. In some embodiments, the immune cell is a helper T lymphocyte that expresses any of the CARs described in this document.

[0306] Prior to genetic expansion and modification, a source of cells can be obtained from a subject by a variety of non-limiting methods. Cells can be obtained from a number of non-limiting sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, Petition 870260028237, dated 03 / 25 / 2026, pp. 956 / 1082 136 / 230 thymus tissue, tissue from a site of infection, ascites, pleural effusion, splenic tissue, and tumors. In some modalities, any number of T cell lines available and known to those skilled in the technique can be used. In some modalities, the cells may be derived from a healthy donor, a patient diagnosed with cancer, or a patient diagnosed with an infection. In some modalities, the cells may be part of a mixed population of cells exhibiting different phenotypic characteristics.

[0307] Cell lines obtained from a T cell transformed according to any of the methods described above are also provided in this document. Modified cells resistant to immunosuppressive treatment are also provided in this document. In some embodiments, a cell isolated according to the description comprises a polynucleotide encoding a CAR.

[0308] The immune cells described can be activated and expanded, before or after genetic modification of T cells, using methods as generally described, for example, without limitation, in US Patents Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and Publication of US Patent Application No. 20060121005. T cells can be expanded in vitro or in vivo. Generally, the T cells described can be expanded, for example, by contact with an agent that stimulates a CD3 TCR complex and a co-stimulatory molecule on the surface of the T cells to create an activation signal for the T cell. For example, chemicals such as the calcium ionophore A23187, phorbol 12-myristate 13-acetate (PMA), or mitogenic lectins such as phytohemagglutinin (PHA) can be used to create an activation signal for the T cell. Petition 870260028237, dated 03 / 25 / 2026, pp. 957 / 1082 137 / 230

[0309] In some embodiments, T cell populations can be stimulated in vitro by contact with, for example, an anti-CD3 antibody, or its antigen-binding fragment, or an anti-CD2 antibody immobilized on a surface, or by contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore. For co-stimulation of an accessory molecule on the surface of T cells, a ligand that binds the accessory molecule is used. For example, a population of T cells can be brought into contact with an anti-CD3 antibody and an anti-CD28 antibody, under appropriate conditions to stimulate T cell proliferation. The anti-CD3 antibody and an anti-CD28 antibody can be arranged in a sphere or plate or other substrate.Suitable conditions for T cell culture include appropriate media (e.g., Minimum Essential Medium or RPMI 1640 or X-vivo 5 (Lonza)) that may contain factors necessary for proliferation and viability, including serum (e.g., fetal bovine or human serum), interleukin-2 (IL-2), insulin, IFN-γ, IL-4, IL-7, GM-CSF, IL-10, IL-2, IL-15, TGFβ, and TNF, or any other cell growth enhancers known to those skilled in the art. Other cell growth enhancers include, without limitation, surfactant, plasmanate, and reducing agents such as N-acetylcysteine ​​and 2-mercaptoethanol.The media may include RPMI 1640, A1M-V, DMEM, MEM, α-MEM, F12, X-Vivo 1 and X-Vivo 20, Optimizer, with the addition of amino acids, sodium pyruvate and vitamins, without serum or supplemented with an appropriate amount of serum (or plasma) or a defined set of hormones and / or a quantity of cytokines sufficient for the growth and expansion of T cells (e.g., IL-7 and / or IL-15). Antibiotics, e.g., penicillin and streptomycin, are included only in experimental cultures, not in cell cultures that are to be infused into a subject. Target cells are maintained under controlled conditions. Petition 870260028237, dated 03 / 25 / 2026, pp. 958 / 1082 138 / 230 are necessary to support growth, for example, an appropriate temperature (e.g., 37°C) and atmosphere (e.g., air plus 5% CO2). T cells that have been exposed to varying stimulation times may exhibit different characteristics.

[0310] In some embodiments, the cells described can be expanded by co-culture with tissue or cells. The cells can also be expanded in vivo, for example, in the subject's blood after administering the cell to the subject.

[0311] In some embodiments, an isolated cell according to the present description comprises a broken or inactivated gene selected from the group consisting of CD52, CD70, GR, PD-1, CTLA4, LAG3, Tim3, BTLA, BY55, TIGIT, B7H5, LAIR1, SIGLEC10, 2B4, HLA, TCRa and TCRe and / or expresses a CAR, a multistranded CAR and / or a pTα transgene. In some embodiments, an isolated cell comprises polynucleotides encoding polypeptides comprising a multistranded CAR.In some embodiments, the isolated cell according to the present description comprises two disrupted or inactivated genes selected from the group consisting of: CD52 and GR, CD52 and TCRα, CDR52 and TCRβ, CD70 and CD52, CD70 and TCRα, CD70 and TCRβ, GR and TCRα, GR and TCRβ, TCRα and TCRβ, PD-1 and TCRα, PD-1 and TCRβ, CTLA-4 and TCRα, CTLA-4 and TCRβ, LAG3 and TCRα, LAG3 and TCRβ, Tim3 and TCRα, Tim3 and TCRβ, BTLA and TCRα, BTLA and TCRβ, BY55 and TCRα, BY55 and TCRβ, TIGIT and TCRα, TIGIT and TCRβ, B7H5 and TCRα. B7H5 and TCRβ, LAIR1 and TCRα, LAIR1 and TCRβ, SIGLEC10 and TCRα, SIGLEC10 and TCRβ, 2B4 and TCRα, 2B4 and TCRβ and / or expresses a CAR, a multistranded CAR and a pTα transgene.

[0312] In some embodiments, the isolated cell according to the present description comprises three broken or inactivated genes selected from CD52, CD70 and TCRα or CD52, CD70 and TCRβ and / or ex Petition 870260028237, dated 03 / 25 / 2026, pp. 959 / 1082 139 / 230 presses a CAR, a multi-stranded CAR, and a pTa transgene.

[0313] In some embodiments, the TCR becomes non-functional in cells as described by the disruption or inactivation of the TCRa gene and / or TCRe genes. In some embodiments, a method is provided for obtaining modified cells derived from an individual, in which the cells can proliferate independently of the major histocompatibility complex (MHC) signaling pathway. The modified cells, which can proliferate independently of the MHC signaling pathway, susceptible to being obtained by this method, are encompassed within the scope of the present description.The modified cells disclosed in this document can be used to treat patients in need of Graft-versus-Host (GvH) rejection and Graft-versus-Host Disease (GvHD); therefore, within the scope of this description is a method of treating patients in need of Graft-versus-Host (GvH) rejection and Graft-versus-Host Disease (GvHD) comprising treating said patient by administering to said patient an effective quantity of modified cells comprising disrupted or inactivated TCRα and / or TCRβ genes.

[0314] In some modalities, immune cells are manipulated to become resistant to one or more chemotherapeutic drugs. The chemotherapeutic drug may be, for example, a purine nucleotide analog (PNA), thus making the immune cell suitable for cancer treatment by combining adoptive immunotherapy and chemotherapy. Exemplary PNAs include, for example, clofarabine, fludarabine, cyclophosphamide, and cytarabine, alone or in combination. PNAs are metabolized by deoxycytidine kinase (dCK) into PNA mono-, di-, and triphosphate. Their triphosphate forms compete with ATP for DNA synthesis, act as pro-apoptotic agents, and are potent inhibitors of ribonucleotide reductase (RNR), which is involved in the production of trinucleotides. Petition 870260028237, dated 03 / 25 / 2026, pp. 960 / 1082 140 / 230 This document provides CD70-specific CAR-T cells comprising a disrupted or inactivated dCK gene. In some embodiments, dCK knockout cells are made by transfecting T cells using polynucleotides encoding specific TAL-nulcease directed against dCK genes, for example, by mRNA electroporation. CD70-specific dCK knockout CAR-T cells can be resistant to PNAs, including, for example, chlorofarabine and / or fludarabine, and maintain cytotoxic T cell activity towards cells expressing CD70.

[0315] In some embodiments, isolated cells or cell lines of the description may comprise a pTa or a functional variant thereof. In some embodiments, an isolated cell or cell line may be further genetically modified by disruption or inactivation of the TCRa gene. Monoclonal epitopes specific for monoclonal antibodies

[0316] In some embodiments, the extracellular domain of any of the CD70-specific CARs disclosed in this document may comprise one or more epitopes specific to (i.e., specifically recognized by) a monoclonal antibody. These epitopes are also referred to in this document as mAb-specific epitopes. Exemplary mAb-specific epitopes are disclosed in International Patent Publication No. WO 2016 / 120126, which is incorporated herein in its entirety. In these embodiments, the extracellular domain comprises the VH and VL polypeptides that specifically bind to CD70 and one or more epitopes that bind to one or more monoclonal antibodies (mAbs). CARs comprising mAb-specific epitopes may be single-stranded or multi-stranded.

[0317] The inclusion of specific epitopes for monoantibodies Petition 870260028237, dated 03 / 25 / 2026, pp. 961 / 1082 The use of 141 / 230 clonal elements in the extracellular domain of CARs described in this document allows for the separation and depletion of engineered immune cells expressing CARs. In some embodiments, this feature also promotes the recovery of cells expressing endogenous CD70 that have been depleted by the administration of engineered immune cells expressing CARs.

[0318] Therefore, in some embodiments, the present description refers to a method for separating and / or subjecting manipulated immune cells endowed with CARs comprising mAb-specific epitopes to depletion and a method for promoting the recovery of cells expressing endogenous CD70, such as bone marrow progenitor cells.

[0319] Various epitope-monoclonal antibody couplings can be used to generate CARs comprising monoclonal antibody-specific epitopes; in particular, those already approved for medical use, such as a CD20 / rituximab epitope as a non-limiting example.

[0320] The description also includes methods for separating engineered immune cells endowed with specific CARs for CD70 that express specific epitopes for mAb and therapeutic methods in which the activation of engineered immune cells endowed with these CARs is modulated by depletion of the cells using an antibody that targets the external ligand-binding domain of said CARs. Rituximab Mimotope SEQ ID NO: 293 CPYSNPSLC Palivizumab Epitope SEQ ID NO: 660 NSELLSLINDMPITNDQKKLMSNN Cetuximab Mimotope 1 SEQ ID NO: 603 CQFDLSTRRLKC Mimotope 2 SEQ ID NO: 604 CQYNLSSRALKC Mimotope 3 SEQ ID NO: 605 CVWQRWQKSYVC Mimotope 4 SEQ ID NO: 606 CMWDRFSRWYKC Petition 870260028237, dated 03 / 25 / 2026, pp. 962 / 1082 142 / 230 Nivolumab Epitope 1 SEQ ID NO: 607 SFVLNWYRMSPSNQTDKLAAFPEDR Epitope 2 SEQ ID NO: 608 SGTYLCGAISLAPKAQIKE QBEND-10 Epitope 1 SEQ ID NO: 609 ELPTQGTFSNVSTNVS Epitope 2 SEQ ID NO: 295 ELPTQGTFSNVSTNVSPAKPTTTA Alemtuzumab Epitope SEQ ID NO: 610 GQNDTSQTSSPS

[0321] In some embodiments, the CAR-T cell comprises a polynucleotide encoding a suicide polypeptide, such as, for example, RQR8. See, for example, WO2013153391A, which is incorporated herein by reference in its entirety. In CAR-T cells comprising the polynucleotide, the suicide polypeptide is expressed on the surface of a CAR-T cell. In some embodiments, the suicide polypeptide comprises the amino acid sequence indicated in SEQ ID NO: 291. CPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCSGGGGSPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRRVCKCPRPVV (SEQ ID NO: 291).

[0322] The suicide polypeptide may also comprise a signal peptide at the amino terminus - for example, MGTSLLCWMALCLLGADHADA (SEQ ID NO: 611). In some embodiments, the suicide polypeptide comprises the amino acid sequence indicated in SEQ ID NO: 292, which includes the signal sequence from SEQ ID NO: 611. MGTSLLCWMALCLLGADHADACPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCSGGGGSPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRRVCKCPRPVV (SEQ ID NO: 292).

[0323] In some embodiments, suicide polypeptide comprises the amino acid sequence of SEQ ID NO: 611 Petition 870260028237, dated 03 / 25 / 2026, pp. 963 / 1082 143 / 230

[0324] When the suicide polypeptide is expressed on the surface of a CAR-T cell, rituximab binding to the R epitopes of the polypeptide causes cell lysis. More than one rituximab molecule can bind per polypeptide expressed on the cell surface. Each R epitope of the polypeptide can bind a separate rituximab molecule. Deletion of CD70-specific CAR-T cells can occur in vivo, for example, by administering rituximab to a patient. The decision to delete the transferred cells may arise from undesirable effects being detected in the patient that are attributable to the transferred cells, such as, for example, when unacceptable levels of toxicity are detected.

[0325] In some embodiments, after administration to a patient, engineered immune cells expressing on their cell surface any of the CD70-specific CARs described in this document may reduce, kill, or lyse cells expressing endogenous CD70 from the patient. In one embodiment, a percent reduction or lysis of endogenous CD70-expressing cells or cells of a CD70-expressing cell line by engineered immune cells expressing any of the CD70-specific CARs described in this document is at least or greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.In one embodiment, a percent reduction or lysis of endogenous cells expressing CD70 or cells of a cell line expressing CD70 by manipulated immune cells expressing any of the CD70-specific CARs described in this document is about 5% to about 95%, about 10% to about 95%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 90%, about 20% to about 80%, about 20%. Petition 870260028237, dated 03 / 25 / 2026, pp. 964 / 1082 144 / 230 to about 70%, about 20% to about 60%, about 20% to about 50%, about 25% to about 75%, or about 25% to about 60%. In one embodiment, the cells expressing endogenous CD70 are bone marrow cells that express endogenous CD70.

[0326] In one embodiment, the percent reduction or lysis of target cells, for example, a cell line expressing CD70, by engineered immune cells expressing on their cell surface membrane a CD70-specific CAR as described can be measured using the assay disclosed in this document. Method for separating CAR-positive immune cells

[0327] In one aspect, methods are provided for in vitro separation of a population of immune cells, wherein a subset of the immune cell population comprises engineered immune cells expressing any of the CD70-specific CARs comprising monoclonal antibody-specific epitopes described in this document. The method comprises contacting the immune cell population with an epitope-specific monoclonal antibody and selecting the immune cells that bind to the monoclonal antibody to obtain a population of engineered immune cells expressing CD70-specific CARs.

[0328] In some embodiments, the aforementioned monoclonal antibody specific for the aforementioned epitope is optionally conjugated to a fluorophore. In this embodiment, the step of selecting cells that bind to the monoclonal antibody can be performed by Fluorescence-Activated Cell Separation (FACS). In some embodiments, the aforementioned monoclonal antibody specific for the aforementioned epitope is optionally conjugated to a magnetic particle. In this embodiment, the step of selecting cells that bind to the monoclonal antibody can be performed by Magnetically Activated Cell Separation (MACS).

[0329] In some forms, the extracellular binding domain Petition 870260028237, dated 03 / 25 / 2026, pp. 965 / 1082 The CAR extracellular binding domain (CAR) comprises a mAb-specific epitope from one or more of the SEQ IDs NO: 294 or 601-610. In some embodiments, the CAR extracellular binding domain comprises a mAb-specific epitope from SEQ ID NO: 609. In some embodiments, the CAR extracellular binding domain comprises a mAb-specific epitope from SEQ ID NO: 295. In some embodiments, the CAR extracellular binding domain comprises a mAb-specific epitope from SEQ ID NO: 609 and the antibody used to contact the immune cell population is QBEND-10. In some embodiments, the CAR extracellular binding domain comprises a mAb-specific epitope from SEQ ID NO: 295 and the antibody used to contact the immune cell population is QBEND-10.

[0330] In some embodiments, the extracellular binding domain of CAR comprises an mAb-specific epitope of SEQ ID NO: 294. In some embodiments, the extracellular binding domain of CAR comprises an mAb-specific epitope of SEQ ID NO: 294 and the antibody used to engage the immune cell population is Rituximab.

[0331] In some embodiments, the CAR-expressing immune cell population obtained using the method for separating CAR-expressing immune cells described above comprises at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of CAR-expressing immune cells. In some embodiments, the CAR-expressing immune cell population for CD70 obtained using the method for separating CAR-expressing immune cells described above comprises at least 85% of CAR-expressing immune cells.

[0332] According to the description, the cells to be administered to the recipient can be enriched in vitro from the source population. The methods of expanding source populations are Petition 870260028237, dated 03 / 25 / 2026, pp. 966 / 1082 146 / 230 well known in the art and may include selecting cells expressing an antigen, such as CD34 antigen, using combinations of density centrifugation, immunomagnetic bead purification, affinity chromatography and fluorescence-activated cell separation, known to those skilled in the art.

[0333] Flow cytometry is widely used in the technique and is a well-known method among those skilled in the art for separating and quantifying specific cell types in a cell population. In general, flow cytometry is a method for quantifying structural components or features of cells primarily by optical means. Since different cell types can be distinguished by quantifying structural features, flow cytometry and cell separation can be used to count and separate cells of different phenotypes in a mixture.

[0334] Flow cytometry analysis involves two basic steps: 1) labeling selected cell types with one or more identified markers and 2) determining the number of labeled cells relative to the total number of cells in the population.

[0335] The first method of labeling cell types is by binding labeled antibodies to markers expressed by the specific cell type. Antibodies are either directly labeled with a fluorescent compound or indirectly labeled using, for example, a second fluorescently labeled antibody that recognizes the first antibody.

[0336] In some modalities, the method used to separate immune cells expressing a CAR is Magnetic Activation Cell Separation (MACS). Magnetic activation cell separation (MACS) is a method for separating various cell populations depending on their surface antigens (CD molecules) using superparamagnetic nanoparticles and columns. It is necessary to Petition 870260028237, dated 03 / 25 / 2026, pp. 967 / 1082 147 / 230 A few simple steps to obtain pure cell populations. Cells in a single-cell suspension are magnetically labeled with microspheres. The sample is applied to a column composed of ferromagnetic spheres, which are coated with a cell coating, allowing for rapid and gentle cell separation. Unlabeled cells pass through while magnetically labeled cells are retained within the column. The continuous flow can be collected as the unlabeled cell fraction. After a short washing step, the column is removed from the separator and the magnetically labeled cells are eluted from the column.

[0337] In some embodiments, the mAb used in the method to separate immune cells expressing CAR is chosen from among alemtuzumab, ibritumomab tiuxetane, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and / or ustekinumab. In some embodiments, the mAb referred to is rituximab. In another embodiment, the mAb referred to is QBEND-10.

[0338] In some embodiments, the CAR-T cell comprises a selected epitope within the scFv with a specificity to be recognized by a specific antibody. See, for example, WO2016 / 120216, which is incorporated herein by reference in its entirety.This epitope facilitates the separation and / or depletion of CAR-T cells. The epitope can be selected from any number of epitopes known in the art. In some embodiments, the epitope can be targeted by a monoclonal antibody approved for medical use, such as, for example, without limitation, the CD20 epitope. 148 / 230 known for rituximab. In some embodiments, the epitope comprises the amino acid sequence CPYSNPSLC (SEQ ID NO: 293)

[0339] In some embodiments, the epitope is located within the CAR. For example, without limitation, the epitope may be located between the scFv and the hinge of a CAR. In some embodiments, two instances of the same epitope, separated by peptide linkers, may be used in the CAR. For example, the polypeptide comprising the amino acid sequence indicated in SEQ ID NO: 294 or SEQ ID NO: 609 or SEQ ID NO: 295 may be used within a CAR, located between the variable light chain region and the hinge. GSGGGGSCPYSNPSLCSGGGGSCPYSNPSLCSGGGGS (SEQ ID NO: 294) ELPTQGTFSNVSTNVS (SEQ ID NO: 609) ELPTQGTFSNVSTNVSPAKPTTTA (SEQ ID NO: 295)

[0340] In some embodiments, the extracellular binding domain of CAR comprises the following sequence V1-L1-V2-(L)x-Epitope1-(L)x-; V1-L1-V2-(L)x-Epítopo1-(L)x-Epítopo2-(L)x-; V1-L1-V2-(L)x-Epítopo1-(L)x-Epítopo2-(L)x-Epítopo3-(L)x-; (L)x-Epítopo1-(L)x-V1-L1-V2; (L)x-Epítopo1-(L)x-Epítopo2-(L)x-V1-L1-V2; Epítopo1-(L)x-Epítopo2-(L)x-Epítopo3-(L)x-V1-L1-V2; (L)x-Epítopo1-(L)x-V1-L1-V2-(L)x-Epítopo2-(L)x; (L)x-Epítopo1-(L)x-V1-L1-V2-(L)x-Epítopo2-(L)x-Epítopo3-(L)x-; (L)x-Epítopo1-(L)x-V1-L1-V2-(L)x-Epítopo2-(L)x-Epítopo3-(L)x-Epítopo4(L)x-; (L)x-Epítopo1-(L)x-Epítopo2-(L)x-V1-L1-V2-(L)x-Epítopo3-(L)x-; (L)x-Epítopo1-(L)x-Epítopo2-(L)x-V1-L1-V2-(L)x-Epítopo3-(L)x-Epítopo4(L)x-; V1-(L)x-Epítopo1-(L)x-V2; Petição 870260028237, de 25 / 03 / 2026, pág. 969 / 1082 149 / 230 V i-(L)x-Epítopo1-(L)x-V2-(L)x-Epítopo2-(L)x; V i-(L)x-Epítopo1-(L)x-V2-(L)x-Epítopo2-(L)x-Epítopo3-(L)x; V i-(L)x-Epitope1-(L)x-V2-(L)x-Epitope2-(L)x-Epitope3-(L)x-Epitope4-(L)x; (L)x-Epitope1-(L)x-Vi-(L)x-Epitope2-(L)x-V2; or, (L)x-Epitope1-(L)x-Vi-(L)x-Epitope2-(L)x-V2-(L)x-Epitope3-(L)x; in which, Vi is Vl and V2 is Vh or Vi is Vh and V2 is Vl; Li is a suitable peptide linker to link the Vh chain to the Vl chain; L is a peptide ligand comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain may be identical to or different from another occurrence of L in the same extracellular binding domain which, in the embodiments, comprises or is SGGGG (SEQ ID NO: 614), GGGGS (SEQ ID NO: 615) or SGGGGS (SEQ ID NO: 616) ex is 0 or 1 or 2 and each occurrence of x is selected independently of the others; and, Epitope 1, Epitope 2, Epitope 3, and Epitope 4 are mAb-specific epitopes and may be identical or different, where Vh is a variable heavy chain fragment and Vl is a variable light chain fragment. In some embodiments, Epitope 1, Epitope 2, and Epitope 4 are mAb-specific epitopes with an amino acid sequence of SEQ ID NO:293, and Epitope 3 is mAb-specific epitopes with an amino acid sequence of SEQ ID NO:295.

[0341] In some embodiments, the extracellular binding domain of CAR comprises the following sequence Vi-Li-V2-(L)x-Epitope1-(L)x-; Vi-Li-V2-(L)x-Epitope1-(L)x-Epitope2-(L)x-; Vi-Li-V2-(L)x-Epitopoi-(L)x-Epitope2-(L)x-Epitope3-(L)x-; Petition 870260028237, dated 03 / 25 / 2026, pp. 970 / 1082 150 / 230 (L)x-Epitope1-(L)x-Vi-Li-V2; (L)x-Epitope1-(L)x-Epitope2-(L)x-Vi-Li-V2; Epitope1-(L)x-Epitope2-(L)x-Epitope3-(L)x-Vi-Li-V2; (L)x-Epitope1-(L)x-Vi-Li-V2-(L)x-Epitope2-(L)x; (L)x-Epítopo1-(L)x-Vi-Li-V2-(L)x-Epítopo2-(L)x-Epítopo3-(L)x-; (L)x-Epítopo1-(L)x-Vi-Li-V2-(L)x-Epítopo2-(L)x-Epítopo3-(L)x-Epítopo4(L)x-; (L)x-Epítopo1-(L)x-Epítopo2-(L)x-Vi-Li-V2-(L)x-Epítopo3-(L)x-; (L)x-Epítopo1-(L)x-Epítopo2-(L)x-Vi-Li-V2-(L)x-Epítopo3-(L)x-Epítopo4(L)x-; V i-(L)x-Epítopo1-(L)x-V2; V i-(L)x-Epítopo1-(L)x-V2-(L)x-Epítopo2-(L)x; V i-(L)x-Epítopo1-(L)x-V2-(L)x-Epítopo2-(L)x-Epítopo3-(L)x; V i-(L)x-Epítopo1-(L)x-V2-(L)x-Epítopo2-(L)x-Epítopo3-(L)x-Epítopo4-(L)x; (L)x-Epítopo1-(L)x-Vi-(L)x-Epítopo2-(L)x-V2; ou, (L)x-Epítopo1-(L)x-Vi-(L)x-Epítopo2-(L)x-V2-(L)x-Epítopo3-(L)x; in that, Vi is Vl and V2 is Vh or Vi is Vh and V2 is Vl; This is a peptide ligand suitable for binding Vh to Vl; L is a peptide ligand comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain may be identical to or different from another occurrence of L in the same extracellular binding domain which, in the embodiments, comprises or is SGGGG (SEQ ID NO: 614), GGGGS (SEQ ID NO: 615) or SGGGGS (SEQ ID NO: 616) ex is 0 or 1 or 2 and each occurrence of x is selected independently of the others; and, Epitope 1, Epitope 2, Epitope 3, and Epitope 4 are specific epitopes for mAb and may be identical or different, and in which Petition 870260028237, dated 03 / 25 / 2026, pp. 971 / 1082 151 / 230 Vh is a variable heavy chain fragment and Vl is a variable light chain fragment. In some embodiments, Epitope 1, Epitope 2, and Epitope 4 are mAb-specific epitopes with an amino acid sequence of SEQ ID NO:293, and Epitope 3 is mAb-specific epitopes with an amino acid sequence of SEQ ID NO:609.

[0342] In some embodiments, the extracellular binding domain of CAR comprises the following sequence V1-L1-V2-(L)x-Epitope1-(L)x-Epitope2-(L)x-; or, (L)x-Epitope1-(L)x-V1-L1-V2-(L)x-Epitope2-(L)x-Epitope3-(L)x-Epitope4(L)x- where Vi, V2, L1, L, x and Epitope 1, Epitope 2, Epitope 3 and Epitope 4 are defined above.

[0343] In some embodiments, the extracellular binding domain of CAR comprises the following sequence (L)x-Epitope1-(L)x-V1-L1-V2-(L)x-Epitope2-(L)x-Epitope3-(L)x-Epitope4(L)x- where V1, V2, L1, L, x are as defined above and where (L)xEpitope1-(L)x is GGGGSCPYSNPSLCSGGGGSGGGGGS (SEQ ID NO: 617), (L)x-Epitope2-(L)x-Epitope3-(L)x-Epitope4 is GSGGGGSCPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLC (SEQ ID NO: 618) and V1, V2, L1, L, x are as defined above.

[0344] In some embodiments, the epitope-specific antibody can be conjugated with a cytotoxic drug. It is also possible to promote CDC cytotoxicity using engineered antibodies to which complement system components are grafted. In some embodiments, CAR-T cell activation can be modulated by depleting cells using an antibody that recognizes the epitope. THERAPEUTIC APPLICATIONS Petition 870260028237, dated 03 / 25 / 2026, pp. 972 / 1082 152 / 230

[0345] Isolated cells obtained by the methods described above, or cell lines derived from such isolated cells, can be used as a medicine. In some embodiments, such a medicine can be used to treat cancer. In some embodiments, the cancer is Renal Cell Carcinoma, glioblastoma, glioma, such as low-grade glioma, Non-Hodgkin Lymphoma (NHL), Hodgkin Disease (HD), Waldenstrom's macroglobulinemia, Acute Myeloid Leukemia, Multiple Myeloma, diffuse large cell lymphoma, follicular lymphoma, or Non-Small Cell Lung Cancer.

[0346] In some forms, the cancer is of hematopoietic origin, such as lymphoma or leukemia. In some modalities, the cancer is selected from the group consisting of multiple myeloma, malignant plasma cell neoplasm, Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma, Kahler's disease and myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, non-Hodgkin B-cell lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, small lymphocytic lymphoma, lymphoma of mantle cells,Burkitt's lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T-cell / histiocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, cutaneous lymphoma. Petition 870260028237, dated 03 / 25 / 2026, pp. 973 / 1082 153 / 230 primary diffuse large B-cell lymphoma (leg type), EBV-positive diffuse large B-cell lymphoma of the elderly, inflammation-associated diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, HHV8-associated Castleman disease-related large B-cell lymphoma, unclassified B-cell lymphoma with intermediate features between diffuse B-cell lymphoma and Burkitt lymphoma, unclassified B-cell lymphoma with intermediate features between diffuse B-cell lymphoma and classical Hodgkin lymphoma, and other hematopoietic cell-related cancers, e.g., ALL or AML.

[0347] In some embodiments, an isolated cell as described, or a cell line derived from isolated cells, may be used in the manufacture of a drug for the treatment of cancer in a patient in need.

[0348] Methods for treating patients are also provided in this document. In some embodiments, the method comprises providing an immune cell of the description to a patient in need. In some embodiments, the method comprises a step of administering transformed immune cells of the description to a patient in need.

[0349] In some embodiments, T cells of the description may undergo robust T cell expansion in vivo and may persist for an extended period of time.

[0350] The treatment methods described may be for enhancement, cure, or prophylaxis. The method described may be part of autologous immunotherapy or part of allogeneic immunotherapy treatment. The description is particularly suitable for allogeneic immunotherapy. Donor T cells can be transformed into non-alloreactive cells using standard protocols and reproduced. Petition 870260028237, dated 03 / 25 / 2026, pp. 974 / 1082 154 / 230 as needed, thus producing CAR-T cells that can be administered to one or more patients. This CAR-T cell therapy can be made available as a standardized therapeutic product.

[0351] The cells that can be used with the disclosed methods are described in the previous section. The treatment can be used to treat patients diagnosed, for example, with cancer. Cancers that can be treated include, for example, but are not limited to, cancers involving B lymphocytes, including any of the cancers listed above. The types of cancers to be treated with CARs and CAR-T cells described include, among others, certain leukemias or lymphoid malignancies. Adult tumors / cancers and pediatric tumors / cancers are also included. In some modalities, the treatment may be in combination with one or more cancer therapies selected from the antibody therapy group, chemotherapy, cytokine therapy, dendritic cell therapy, gene therapy, hormone therapy, laser therapy, and radiotherapy.

[0352] In some embodiments, treatment can be administered to patients undergoing immunosuppressive treatment. In fact, the methods described, in some embodiments, depend on cells or cell populations that have been resistant to at least one immunosuppressive agent due to the inactivation of a gene encoding a receptor for such immunosuppressive agent. In this respect, immunosuppressive treatment should aid the selection and expansion of T cells, as described, within the patient. Administration of cells or cell populations as described can be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, infusion, transfusion, implantation, or transplantation. The compositions described in this document can be administered to a patient subcutaneously, intradermally, intradermally Petition 870260028237, dated 03 / 25 / 2026, pp. 975 / 1082 155 / 230 tumoral, intranodal, intramedullary, intramuscular, by intravenous or intralymphatic injection or infusion or intraperitoneal route. In some embodiments, the cell compositions described are administered by intravenous injection or infusion.

[0353] In some embodiments, the administration of cells or cell populations may comprise the administration of, for example, approximately 10⁴ to approximately 10⁹ cells per kg of body weight, including all whole numbers of cells within those ranges. In some embodiments, the administration of cells or cell populations may comprise the administration of approximately 10⁵ to approximately 10⁶ cells per kg of body weight, including all whole numbers of cells within those ranges. The cells or cell population may be administered in one or more doses. In some embodiments, the aforementioned effective quantity of cells may be administered as a single dose. In some embodiments, the aforementioned effective quantity of cells may be administered as more than one dose over a period of time. The timing of administration is at the discretion of the attending physician and depends on the patient's clinical condition.Cells or cell populations can be obtained from any source, such as the patient, a blood bank, or a donor. Although individual needs vary, determining ideal ranges of effective quantities of a given cell type for a specific disease or condition is within the technique. An effective quantity means a quantity that provides a therapeutic or prophylactic benefit. The dosage administered will depend on the recipient's age, health, and weight, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect. In some modalities, an effective quantity of cells or a composition comprising such cells is administered parenterally. In some... Petition 870260028237, dated 03 / 25 / 2026, pp. 976 / 1082 In 156 / 230 modalities, administration may be intravenous. In some modalities, administration may be done directly by injection into a tumor.

[0354] In some embodiments, the methods involve (a) administering to a subject who has a disease a first dose of allogeneic CAR-T cells. In some embodiments, the first dose contains about 1χ104 cells, about 5χ104 cells, about 1χ10 cells, about 5χ105 cells, about 1χ106 cells, about 5χ10 cells, about 6χ106 cells, about 1χ107 cells, about 6χ10 cells, about 1χ108, about 1.8χ108 cells or about 4.8χ108 cells. In some embodiments, the methods further involve (b) administering to the subject a subsequent dose of CAR-T cells at a time that is at least or more than about 5 weeks after and less than about 24 weeks after the start of said administration in (a).

[0355] In some embodiments, a subject with relapsing / refractory disease (e.g., relapsing / refractory RCC) receives a first dose and a subsequent dose of allogeneic CAR-T cells, each containing approximately 6χ106 cells, and the subsequent dose of CAR-T cells in (b) is administered approximately 99 days after the start of administration in (a).

[0356] In some embodiments, the methods further involve the administration of subsequent or follow-on additional doses, such that a first and multiple subsequent doses are administered, for example, according to the dosage amounts and time schedules as specified for the first dose and subsequent doses. In some embodiments, the first of one or more subsequent doses is administered at a time that is at least or more than 5 weeks after the start of administration of the subsequent dose. In some embodiments, the administration of the first dose is... Petition 870260028237, dated 03 / 25 / 2026, pp. 977 / 1082 157 / 230 ra, subsequent and subsequent doses include the administration of at least three of the doses in or about 5 weeks. In some embodiments, the subsequent dose is administered approximately 16 weeks after the start of the first dose, and an additional subsequent dose is administered at week 17 after the start of the first dose. In some embodiments, additional subsequent doses are administered at week 17 and / or week 34 after the start of the first dose.

[0357] In some respects, the time of administration of the subsequent dose(s) is still that in which the subject does not exhibit an immune response, for example, does not exhibit a detectable adaptive host immune response to CAR-T from the aforementioned first (or previous) dose.

[0358] In some embodiments, the time between administration of the first dose (initial dose), for example, the start of administration of the first or previous dose and the start of administration of the subsequent dose (for example, the start of administration of the subsequent dose) is greater than about 4 weeks, for example, greater than about 5, 6, 7, 8, or 9 days, for example, greater than about 20 weeks, for example, between about 9 and about 35 weeks, between about 14 and about 28 weeks, between 15 and 27 weeks, or between 16 weeks and about 18 weeks; and / or at or about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 weeks. In some modalities, the administration of the subsequent dose (e.g., initiation of the dose) is greater than approximately 5 weeks after and less than approximately 24 weeks after the administration of the first dose or the previous dose (e.g., initiation of doses).In some modalities, the administration of the subsequent dose is initiated 17 weeks after the start of the first dose. In some modalities, the time between the administration of the first dose and the subsequent dose (e.g., initiation of doses) or an. Petition 870260028237, dated 03 / 25 / 2026, pp. 978 / 1082 158 / 230 doses and the next subsequent dose is greater than approximately 5 weeks and less than approximately 24 weeks, such as between 10 and 24 weeks, such as approximately 17 weeks. In some embodiments, the time between administration of the first dose and the subsequent dose (e.g., initiation thereof) is approximately 17 weeks.

[0359] In some embodiments of the description, the cells are administered to a patient in conjunction with (e.g., before, simultaneously with, or after) any number of relevant treatment modalities, including, but not limited to, treatment with agents such as monoclonal antibody therapy, CCR2 antagonist (e.g., INC-8761), antiviral therapy, cidofovir and interleukin-2, cytarabine (also known as ARA-C), or treatment with natalizimab for MS patients or treatment with efaliztimab for psoriasis patients or other treatments for PML patients.In some embodiments, CD70-specific CAR-T cells are administered to a patient in conjunction with one or more of the following: an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, or PF-06801591), an anti-PD-L1 antibody (e.g., avelumab, atezolizumab, or durvalumab), an anti-OX40 antibody (e.g., PF-04518600), an anti-4-1BB antibody (e.g., PF05082566), an anti-MCSF antibody (e.g., PD-0360324), an anti-GITR antibody, and / or an anti-TIGIT antibody. In some embodiments, a CD70-specific CAR comprising the amino acid sequence indicated in SEQ ID NO: 319 or 327 is administered to a patient in conjunction with the anti-PD-L1 antibody avelumab.In other modalities, the T cells described may be used in combination with chemotherapy, radiation, immunosuppressive agents such as cyclosporine, azathioprine, methotrexate, mycophenolate and FK506, antibodies or other immunoablative agents such as CAMPATH, anti-CD3 antibodies or other antibody therapies, cytoxi. Petition 870260028237, dated 03 / 25 / 2026, pp. 979 / 1082 159 / 230 na, fludaribine, cyclosporine, FK506, rapamycin, mycoplienolic acid, steroids, FR901228, cytokines and / or irradiation. These drugs inhibit the calcium-dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit p70S6 kinase, which is important for growth factor-induced signaling (rapamycin) (Henderson, Naya et al. 1991; Liu, Albers et al. 1992; Bierer, Hollander et al. 1993). In other embodiments, the T cells described may be used in combination with Tyrosine Kinase Receptor inhibitors, such as Midostaurin, Sunitinib and axitanib, mTOR inhibitors, such as Rapamycin and Everolimus, epigenetic modulators, such as Vormostat, proteasome inhibitors such as Bortezomib, immunomodulatory agents such as Erismodegib and PF-04449913 inhibitors or Isocitrate Dehydrogenase (IDH) inhibitors, such as AG-120 and AG-221.In another embodiment, the cell compositions described are administered to a patient in conjunction with (e.g., before, simultaneously with, or after) bone marrow transplantation, ablative T-cell therapy using chemotherapeutic agents such as fludarabine, external beam radiotherapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some embodiments, the cell compositions described are administered after ablative B-cell therapy, such as CD20-reacting agents, for example, Rituxan. For example, in some embodiments, subjects may undergo standard high-dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, after transplantation, subjects receive an infusion of the expanded immune cells described. In some embodiments, the expanded cells are administered before or after surgery.

[0360] In some embodiments, methods are provided for the depletion of manipulated immune cells expressing specific CARs. Petition 870260028237, dated 03 / 25 / 2026, pages 980 / 1082 160 / 230 for CD70 of a subject who received the aforementioned cells. Depletion can be due to inhibition or elimination.

[0361] In one aspect, a method for subjecting engineered immune cells expressing specific CAR for CD70 to depletion comprising a specific epitope for a monoclonal antibody comprises placing said engineered immune cell in contact with a monoclonal antibody specific for the epitope.

[0362] In some embodiments, a method for depleting a subject who has received engineered immune cells expressing CD70-specific CAR comprising a monoclonal antibody-specific epitope involves administering to the subject a monoclonal antibody specific for the epitope. In these embodiments, administration of the epitope-specific monoclonal antibody present in the extracellular domain of CAR to the subject eliminates or inhibits the activity of the subject's engineered immune cells expressing CAR. In one aspect, depletion of engineered immune cells expressing CAR allows recovery of an endogenous population of CD70-expressing cells.

[0363] In one aspect, the description refers to a method for promoting the recovery of endogenous CD70-expressing cells in a subject who has received engineered immune cells expressing on their cell surface a CD70-specific CAR comprising a monoclonal antibody-specific epitope, the method comprising administering an epitope-specific monoclonal antibody to the subject. In some embodiments, the endogenous CD70-expressing cells are endogenous CD70-expressing bone marrow cells. In one aspect, the term recovery refers to an increase in the number of endogenous CD70-expressing cells. The number of endogenous CD70-expressing cells may increase due to increased proliferation of CD70-expressing cells. Petition 870260028237, dated 03 / 25 / 2026, pages 981 / 1082 161 / 230 endogenous and / or due to reduced elimination of endogenous CD70-expressing cells by engineered immune cells expressing CAR. In some embodiments, administration of the monoclonal antibody to the subject subjects the engineered immune cells expressing CAR to depletion and increases the number of endogenous CD70-expressing cells, for example, endogenous CD70-expressing bone marrow progenitor cells, in the subject. In one embodiment, administration of the monoclonal antibody to the subject increases the number of cells expressing endogenous CD70 by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, compared with the number of cells expressing endogenous CD70 before administration of the monoclonal antibody.

[0364] In one aspect, a method is provided for treating a CD70-mediated condition in a subject, the method comprising: (a) administering to the subject engineered immune cells expressing on their cell surface CD70-specific CARs comprising one or more epitopes specific for one or more monoclonal antibodies; and (b) subsequently subjecting the engineered immune cells derived from the subject to depletion by administering one or more epitope-specific monoclonal antibodies to the subject.

[0365] In some embodiments, the mAbs used in the method to subject CAR-expressing immune cells to depletion are selected from among alemtuzumab, ibritumomab tiuxetane, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, bevacizumab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitu Petition 870260028237, dated 03 / 25 / 2026, pages 982 / 1082 162 / 230 mumab, QBEND-10 and / or ustekinumab and combinations thereof.

[0366] In some embodiments, the aforementioned epitope specific for a monoclonal antibody (mAb-specific epitope) is a CD20 epitope or mimotope, for example, SEQ ID NO: 609, SEQ ID NO: 294 or SEQ ID NO: 295, and the mAb specific for the epitope is rituximab.

[0367] In some embodiments, the step of administering a monoclonal antibody to the subject involves infusing the subject with the monoclonal antibody. In some embodiments, the amount of epitope-specific mAb administered to the subject is sufficient to eliminate at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the CAR-expressing immune cells in the subject.

[0368] In some embodiments, the step of administering a monoclonal antibody to the subject involves infusing the subject with 375 mg / m2 of rituximab, once or several times a week.

[0369] In some embodiments, when immune cells expressing CAR comprising a specific mAb epitope (CAR-expressing immune cells) undergo depletion in a CDC assay using epitope-specific mAb, the amount of viable CAR-expressing immune cells decreases, for example, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0370] In some embodiments, a cytotoxic drug is coupled to epitope-specific mAbs that are used to subject CAR-expressing immune cells to depletion. By combining the targeting capabilities of monoclonal antibodies with the cellular scavenging capabilities of cytotoxic drugs, the antibody-drug conjugate (ADC) allows for sensitive discrimination between healthy and diseased tissue when compared to the use of the drug alone. Market approvals have been received for several ADCs; the technology to produce them—particularly in peptide linkers—is Petition 870260028237, dated 03 / 25 / 2026, pages 983 / 1082 163 / 230 presented abundantly in the following technique (Payne, G. (2003) Cancer Cell 3:207-212; Trail et al (2003) Cancer Immunol. Immunother. 52:328-337; Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Del. Rev. 26:151-172;

[0371] In some modalities, the epitope-specific mAb, upon infusion, is pre-conjugated with a molecule capable of promoting complement-dependent cytotoxicity (CDC). Therefore, the complement system assists or complements the ability of antibodies to clear pathogens from the organism. When stimulated by one of several, a cascade activation is triggered, such as a large amplification of the response and activation of the membrane attack complex by cell death. A different molecule can be used to conjugate the mAb, such as glycans [Courtois, A, GacBreton, S., Berthou, C, Guezennec, J., Bordron, A. and Boisset, C. (2012). Complement-dependent cytotoxicity activity of therapeutic antibody fragments is acquired by immunogenic glycan coupling, Electronic Journal of Biotechnology ISSN: 07173458; http: / / www.ejbiotechnology.info DOI: 10.2225 / voll5-issue5]. KITS

[0372] The description also provides kits for use in the instant methods. The kits in the description include one or more containers comprising a polynucleotide encoding a specific CAR for CD70 or a engineered immune cell comprising a polynucleotide encoding a specific CAR for CD70, as described in this document, and instructions for use in accordance with any of the methods in the description described in this document. Generally, these instructions comprise a description of the administration of the engineered immune cell for the therapeutic treatments described above. The kit may include one or more agents for lympho Petition 870260028237, dated 03 / 25 / 2026, pages 984 / 1082 164 / 230 depletion (e.g., alemtuzumab, cytoxan, fludarabine, cyclophosphamide, or temozolomide).

[0373] Instructions relating to the use of engineered immune cells as described in this document generally include information regarding dosage, dosing schedule, and route of administration for the intended treatment. Containers may be unit doses, bulk packages (e.g., multi-dose packs), or subunit doses. Instructions provided in the kits described are typically written instructions on a label or package insert (e.g., a sheet of paper included in the kit), but machine-readable instructions (e.g., instructions within a magnetic or optical storage disk) are also acceptable. In some embodiments, the containers are identifiable (e.g., by label, barcode, or radio frequency identification (RFID)), traceable, or printed with a machine-readable container identifier.

[0374] The kits described here are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., Myler bag or sealed plastic bag) and the like. In some embodiments, the container (e.g., plastic bag) is suitable for intravenous infusion. Packaging for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., a sprayer) or an infusion device, such as a mini-pump, is also contemplated. A kit may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a cap that can be pierced by a hypodermic injection needle). The container may also have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a cap that can be pierced by a Petition 870260028237, dated 03 / 25 / 2026, pages 985 / 1082 165 / 230 hypodermic injection needle). At least one active agent in the composition is a specific CAR for CD70. The container may additionally comprise a second pharmaceutically active agent.

[0375] The kits may optionally provide additional components, such as stoppers and interpretive information. Typically, the kit comprises a container and a label or leaflet associated with the container.

[0376] The following examples are offered for illustrative purposes only and are not intended to limit the scope of the description in any way. In fact, various modifications of the description, beyond those shown and described herein, will become apparent to those skilled in the art from the preceding description and are within the scope of the appended claims.

[0377] The deposit was made in accordance with the provisions of the Budapest Treaty on International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and Regulations below (Budapest Treaty). This ensures the maintenance of a viable culture of the deposit for 30 years from the date of filing. The deposit will be made available by the ATCC in accordance with the terms of the Budapest Treaty and subject to an agreement entered into between Pfizer, Inc.and ATCC, which guarantees the permanent and unrestricted availability of the deposit crop progeny to the public upon issuance of the relevant U.S. patent or upon submission to public inspection of any U.S. or foreign patent application, whichever occurs first, and ensures the availability of the progeny as determined by the U.S. Patent and Trademark Commission entitled to do so, pursuant to Section 122 of Title 35 of the U.S. Code and related Commissioner regulations (including 1.14 of Title 37 of the Code of Federal Regulations with specific reference to 886 OG 638). Petition 870260028237, dated 03 / 25 / 2026, pages 986 / 1082 166 / 230

[0378] The assignee of this application has agreed that if a crop of the deposited materials dies, is lost or destroyed when grown under suitable conditions, the materials will be immediately replaced upon notification by others of the same. The availability of the deposited material shall not be construed as a license to practice the description in contravention of the rights granted under the authority of any government in accordance with its patent laws. EXAMPLES Example 1. Generation of specific CAR-T cells for CD70

[0379] The following codon-optimized CAR sequences for CD70 listed in Table 5 below were synthesized and subcloned into the following lentiviral vectors pLVX-EF1a-TurboGFP-P2ACD70 CAR (Clontech) or pCLS-EF1a-BFP-P2A-CD70 CAR (Cellectis) using Xmal (5') and MluI (3') restriction sites (thus cloning from the CAR following the P2A site). Table 5: Specific CARs for CD70 copies CAR Amino Acid Sequence of CAR Components 31H1 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYGFSWVRQAPGQGLEWMGGIIPIFGSANYAQKFQGRVTITADKSTSTVYMELISLRSEDTAVYYCAR- GGSSSPFAYWGQG- TLVTVSSGGGGSGGGGSGGGSGGGGSDIVMTQNPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQSPRLLIYKISNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCMQATQFPLTIGGGSKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDF ACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 311) CD8a signal peptide; 31H1 VH; Peptide ligand GS; 31H1 VL; Peptide ligand GS; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD Petition 870260028237, dated 03 / 25 / 2026, pp. 987 / 1082 167 / 230 CAR Amino Acid Sequence of CAR Components 63B2 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYGFSWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTVFMELISLRSEYTAVYYCAR- GGSSSPFAYWGQG- TLVTVSSGGGGSGGGGSGGGGSGGGGSSDIVMTQTPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQSPRLLIYKISNRFSGVPDRFSGSGAGTDFTLKISRVEAEDVGVYYCMQATQFPLTIGGGSKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDF ACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 312) CD8a signal peptide; 63B2 VH; Peptide linker GS; 63B2 VL; Peptide linker GS; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD 40E3 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWNWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLRSVTAADTAVYYCARDI RTWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWFQQKPGKAPKSLIYAASSLQSGVPSKFSGSGSGTDFTLTISSLQPEDFATYYC QQYNSYPLTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 313) CD8a signal peptide; 40E3 VH; GS peptide ligand; 40E3 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pages 988 / 1082 168 / 230 CAR Amino Acid Sequence of CAR Components 42C3 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFRNSWMSWVRQAPG KG LEWVANIKRDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDQTGSFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDENTYLNWFQQRPGQSLRRLIYQVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCMQGTYWPPTFGGGTKVEIKTTTPAPRPP TPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 314) CD8a signal peptide; 42C3 VH; GS peptide ligand; 42C3 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD 45F11 MALPVTALLLPLALLLHAARPQVQLRGSGPGLVKPSETLSLTCTVSDDSISVYYWSWIRQPAGKGLEWIGRVYSSGNINYNPSLESRVTMSVDTSKSRFSLNLSSVTAADTAVYYCARGL DAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGGGGSEIVMTQSPATLSMSLGERATLSCRASQSVSSSLAWYQQKPGQAPRLLIYGASTRATGIPARFGGSGSGTEFTLTISSLQSEDFA- VYYCQQYINWPH FGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 315) CD8a signal peptide; 45F11 VH; GS peptide ligand; 45F11 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 989 / 1082 169 / 230 CAR Amino Acid Sequence of CAR Components 64F9 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGESLRLSCEVSGFTFTSYAMSWVRQVPGKGLEWVSIISGVAFTTYYADSVKGRFTISRDHSKNTLYLQMNGLRAEDTAVYYCVKVD GEVYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKILIYGASNLETGVPSRFSGSGSGTDFTFAISSLQPEDVATYY CQQYDNFPITFGQGTRLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 316) CD8a signal peptide; 64F9 VH; GS peptide ligand; 64F9 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD 72C2 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCEASGGTFITYAISWVRQAPGQGLEWMGGIIPFFGTANYAQKFQGRVTITADKSTSTASMELRSLRSEDTAMYYCAQWE LFFFDFWGQGTPVTVSSGGGGSGGGGSGGGGSGGGGGSEIVMTQSPDTLSVSPGERAILSCRASQSVSSNLAWYQQKPGQAPRLLIYSASTRASGIPARFSGSGSGTEFTLSISSLQSEDFA- VYYCQQYDNWPPLTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 317) CD8a signal peptide; 72C2 VH; GS peptide ligand; 72C2 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 990 / 1082 170 / 230 CAR Amino Acid Sequence of CAR Components 2F10 MALPVTALLLPLALLLHAARPAVQLVESGGGLVQPGGSLRLSCAASGFTFTYYSMNWVRQAPG KGLEWVSHISIRSSTIYFADSAKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARGSGWYGDYFDYWGQGTLVTVSSGGGGSGGGGGSGGGGSGGGGSEIVLT QSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQQPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAIYYCQQYGSSPLTFGGGTKVEIK TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 318) CD8a signal peptide; 2F10 VH; GS peptide ligand; 2F10 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD 4F11 MALPVTALLLPLALLLHAARPQVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVTWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKTQVVLTMTNMDPVDTATYYCARIRDYYDISSYYDYWG QGTLVSVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSAMSASVGDRVTITCRASQDISNYLAWFQQKPGKVPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLLPEDFATYYCLQLNSFPFTFGGGTKVEIN TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 319) CD8a signal peptide; 4F11 VH; GS peptide ligand; 4F11 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 991 / 1082 171 / 230 CAR Amino Acid Sequence of CAR Components 10H10 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAVSGFTFSNHNIHWVRQAPGKGLEWISYISRSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARDHA QWYGMDVWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKVLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT YYCQQAFSFPFTFGPGTKVDIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 320) CD8a signal peptide; 10H10 VH; GS peptide ligand; 10H10 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD 17G6 MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCVASGFTFFSYWMSWVRQAPG KG LEWVASIKQDGSEKYYVDSVKGRFTISRDNAKNSVYLQMNSLRAEDTGVYYCAREGVNWGWRLYWHFDLWG RGTLVTVSSGGGGSGGGGSGGGGSGGGGSSDIVMTQSPDSLAVSLGERATINCKSSQSVLYSYNNKNYVAWYQQKPGQPPNLLIFWASTRESGVPDRFSGSGSGTDFTLTISSLQAED- VAVYYCQQYYSTLTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 321) CD8a signal peptide; 17G6 VH; GS peptide ligand; 17G6 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pages 992 / 1082 172 / 230 CAR Amino Acid Sequence of CAR Components 65E11 MALPVTALLLPLALLLHAARPEVQVVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSHSSISRGNIYFADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARGSGWYGDYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGERVTLSCRASQSVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFA VYYCQQYGSSPLTFGGGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 322) CD8a signal peptide; 65E11 VH; GS peptide ligand; 65E11 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD P02B10 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGFAFSNYAMSWVRQAPGKGLEWVSAIRGGGGSTYYADSVKGRFTI SRDNSKNTLYLQMNSLRAEDTAVYYCARDFISGTWYPDYWGQG- TLVTVSSGGGGSGGGGSGGGGSGGGGSELQ SVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDE- ADYYCAAWDDSLSGVVFGGGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 323) CD8a signal peptide; P02B10 VH; GS peptide ligand; P02B10 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 993 / 1082 173 / 230 CAR Amino Acid Sequence of CAR Components P07D03 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYRFTSYWIGWVRQMPGKG LEWM GSIYPDDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSTVDYPGYSYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQ SVLTQPPSASGTPGQRVTISCSGSRSNIGSNYVYWYQQLPGTAPKLLIYRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCASWDGSLSAVVFGTGTKLTVLTTTPA- PRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 324) CD8a signal peptide; P07D03 VH; GS peptide ligand; P07D03 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD P08A02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYTFTNYWIAWVRQMPGKG LEWM GIIYPDGSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARDITSWYYGEPAFDIWGQG- TLVTVSSGGGGSGGGGSGGGGSGGGGSELQ SVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYRNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDE- ADYYCATWDDSLGSPVFGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 325) CD8a signal peptide; P08A02 VH; GS peptide ligand; P08A02 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 994 / 1082 174 / 230 CAR Amino Acid Sequence of CAR Components P08E02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYSFTSSWIGWVRQMPGKG LEWM - LQPEDFATYYCQQSYSTTMWTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL- PPR (SEQ ID NO: 326) CD8a signal peptide; P08E02 VH; GS peptide ligand; P08E02 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD P08F08 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYGFTSYWIGWVRQMPGKG LEWM GIIHPDDSDTKYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCASSYLRGLWGGYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQ SVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYGDYQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATRDDSLSGSVVFGTGT- KLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 327) CD8a signal peptide; P08F08 VH; GS peptide ligand; P08F08 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 995 / 1082 175 / 230 CAR Amino Acid Sequence of CAR Components P08G02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYTFPSSWIGWVRQMPGKG LEWM GIIYPDTSHTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARASYFDRGTGYSSWWMDVWGQG- TLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRVTITCRASQSIYDYLHWYQQKPGKAPKLLIYDASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPLFTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFA CDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 328) CD8a signal peptide; P08G02 VH; Peptide linker GS; P08G02 VL; Peptide linker GS; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD P12B09 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGFTFSQYSMSWVRQAPGKGLEWVSAISGGGVSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASDISDS GGSHWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRVTITCRASQYIGRYLNWYQQKRGKAPKLLIHGATSLASGVPSRFSGSGSGTDFTLTISSLQPED FATYYCQQSYSTTSPTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 329) CD8a signal peptide; P12B09 VH; GS peptide ligand; P12B09 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 996 / 1082 176 / 230 CAR Amino Acid Sequence of CAR Components P12F02 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTISGTGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVRAGIDPTASDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQ SVLTQPPSASGTPGQRVTISCSGSTSNIGRNYVYWYQQLPGTAPKLLIYRTNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGRVFGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 330) CD8a signal peptide; P12F02 VH; GS peptide ligand; P12F02 VL; Peptide linker GS; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD P12G07 MALPVTALLLPLALLLHAARPEVQLLESGGGLVQPGGSLRLSCAASGFTFNNFAMSWVRQAPGKGLEWVSGISGSGDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRDIGLGWYSYYLDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELQ SVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKPLIYMNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSAVVFGTGTKLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 331) CD8a signal peptide; P12G07 VH; GS peptide ligand; P12G07 VL; Peptide linker GS; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 997 / 1082 177 / 230 CAR Amino Acid Sequence of CAR Components P13F04 MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGEIIPIFGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARAGWDDSWFDYWGQG- TLVTVSSGGGGSGGGGSGGGGSGGGGSELQ SVLTQPPSASGTPGQRVTISCSGSNSNIGTNYVSWYQQLPGTAPKLLIYRSSRRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDGSLSGHWVFGTGT- KLTVLTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 332) CD8a signal peptide; P13F04 VH; GS peptide ligand; P13F04 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD;CD3Z ISD P15D02 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYSFASYWIGWVRQMPGKG LEWM GVIYPGTSETRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCAKGLSASASGYSFQYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYSASSLHSGVPSRFSGSGSGTDFTLTISS- LQPEDFATYYCQQSYSTTAWTFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL- PPR (SEQ ID NO: 333) CD8a signal peptide; P15D02 VH; GS peptide ligand; P15D02 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD; Petition 870260028237, dated 03 / 25 / 2026, pp. 998 / 1082 178 / 230 CAR Amino Acid Sequence of CAR Components P16C05 MALPVTALLLPLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGYSFTDYWIGWVRQMPGKG LEWM GMISPGGSTTIYRPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCAREMYTGGYGGSWYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELDIQMTQSPSSLSASVGDRVTITCRASQSIGQSLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISS- LQPEDFATYYCQQSYSTPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQAL- PPR (SEQ ID NO: 334) CD8a signal peptide; P16C05 VH; GS peptide ligand; P16C05 VL; GS peptide ligand; CD8a hinge; CD8a TM domain; 41BB ISD; CD3Z ISD

[0380] CARs comprising ScFv based on 10A1, 10E2, 11A1, 11C1, 11D1, 11E1, 12A2, 12C4, 12C5, 12D3, 12D6, 12D7, 12F5, 12H4, 8C8, 8F7, 8F8, 9D8, 9E10, 9E5, 9F4 or 9F8 the sequences are also prepared and comprise sequences indicated in SEQ ID NO: 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600 and 601. Example 2: Jurkat screening for in vitro characterization of CARs for anti-CD70

[0381] Jurkat cells are a lineage of immortalized human T cells that closely resemble primary T cells, expressing CD70 upon activation or transduction. Therefore, these cells were chosen for transduction with CARs to CD70 to study their activation profile. Jurkat cells modified using CRISPR / Cas9 for CD70 knockout (KO Jurkat) or original Jurkat cells (WT Jurkat) were transduced with CARs to CD70. Their autoactivation profile was determined by c...

Claims

1. Chimeric antigen receptor (CAR), characterized in that it comprises an extracellular ligand-binding domain that specifically binds to CD70, a first transmembrane domain, and an intracellular signaling domain, wherein the extracellular ligand-binding domain comprises a variable heavy chain domain comprising amino acid sequences for CDRH1, CDRH2, and CDRH3 and a variable light chain domain comprising amino acid sequences for CDRL1, CDRL2, and CDRL3, wherein: CDRH1 comprises an amino acid sequence selected from SEQ ID NOs: 478-480, CDRH2 comprises an amino acid sequence selected from SEQ ID NOs: 481-482, CDRH3 comprises the amino acid sequence of SEQ ID NO: 483, CDRL1 comprises the amino acid sequence of SEQ ID NO: 562, CDRL2 comprises the amino acid sequence of SEQ ID NO: 563, and CDRL3 comprises the amino acid sequence of SEQ ID NO:

564.

2. A CD70-specific CAR, according to claim 1, characterized in that the intracellular signaling domain comprises a CD3Z signaling domain.

3. A CD70-specific CAR, according to claim 2, characterized in that it further comprises a second intracellular signaling domain.

4. Specific CAR for CD70, according to claim 1, characterized in that the intracellular signaling domain comprises a 4-1BB domain. Petition 870260028237, dated 03 / 25 / 2026, page 1052 / 1082 2 / 3 5. A specific CAR for CD70, according to claim 1, characterized in that it further comprises a stem domain between the extracellular ligand-binding domain and the first transmembrane domain.

6. A specific CAR for CD70, according to claim 5, characterized in that the stem domain is selected from the group consisting of: a human CD8a hinge, an IgG1 hinge and an FcyRII hinge.

7. A specific CAR for CD70, according to claim 1, characterized in that it further comprises a CD20 epitope.

8. A specific CAR for CD70, according to claim 7, characterized in that the CD20 epitope comprises the amino acid sequence shown in SEQ ID NO: 293 or SEQ ID NO: 294 or SEQ ID NO:

609.

9. A specific CAR for CD70, according to claim 1, characterized in that the first transmembrane domain comprises a CD8α chain transmembrane domain.

10. A specific CAR for CD70, according to claim 1, characterized in that the variable domain of the light chain comprises the amino acid sequence of SEQ ID NO: 370 and the variable domain of the heavy chain comprises the amino acid sequence of SEQ ID NO:

371.

11. A specific CAR for CD70, according to claim 1, characterized in that it further comprises a suicide polypeptide.

12. Specific CAR for CD70, according to claim 11, characterized in that the suicide polypeptide comprises RSRQR or R2S. Petition 870260028237, dated 03 / 25 / 2026, pp. 1053 / 1082 3 / 3 13. A specific CAR for CD70, according to claim 1, characterized in that the CAR comprises the amino acid sequence of SEQ ID NO: 527, 596, 635 or 643.

14. A CD70-specific CAR, according to claim 1, characterized in that it comprises another extracellular ligand-binding domain that is not specific for CD70.

15. A CD70-specific CAR according to claim 1, characterized in that the extracellular ligand-binding domain(s), the first transmembrane domain, and the intracellular signaling domain(s) are in a single polypeptide.

16. Genetically modified immune cell, characterized in that it expresses on its cell surface membrane a CAR specific for CD70, according to claims 1 to 15.

17. Pharmaceutical composition, characterized in that it comprises the manipulated immune cell as defined in claim 16.

18. A method for manipulating an immune cell, characterized in that it comprises: a) providing an immune cell; and b) introducing into the cell at least one polynucleotide encoding the said CAR specific for CD70 as defined in claim 1.

Images