Immunoconjugate and uses of it to treat hematological cancer

Description

Immunoconjugate and its uses in treating hematological cancer. Divided from BR 11 2021 015036 6, deposited on 01.02.2020 CROSS-REFERENCE ON RELATED REQUEST

[001] This application claims priority from U.S. Provisional Patent Application 62 / 800,187, filed February 1, 2019, the disclosure of which is incorporated by reference in the present invention in its entirety. SEQUENCE LISTING

[002] The present application contains a Sequence Listing that was submitted electronically in ASCII format and is incorporated into the present invention by reference in its entirety. The electronic copy of the Sequence Listing, created on January 29, 2020, is named 024651_WO003_SL.txt and is 9,833 bytes in size. BACKGROUND OF THE INVENTION

[003] Hematologic malignancies comprise diseases resulting from transformation events that occur in immunological or hematopoietic organs. Lymphoid malignancies arise from the accumulation of neoplastic monoclonal lymphocytes in lymph nodes and organs such as blood, bone marrow, spleen, and liver. Variants of these cancers comprise non-Hodgkin lymphomas (NHLs), including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), Richter transformation lymphoma (RTL), Burkitt lymphoma (BL), lymphoplasmacytoid lymphoma (LPL), Waldenstrom macroglobulinemia (WM), acute lymphocytic leukemia (ALL), and various types of T-cell lymphomas. Acute myeloid leukemia (AML) results from the accumulation of neoplastic myeloid blasts in the bone marrow, blood, central nervous system, and other organs.

[004] Depending in part on the cell of origin (B cell or T cell), Petition 870260064342, dated 06 / 30 / 2026, page 14 / 120 2 / 85 Patients with NHL may experience debilitating constitutional symptoms, lymphadenopathy, and organomegaly that can induce life-threatening organ dysfunction, myelosuppression, and immunocompromise that can result in susceptibility to infection and bleeding, and / or cutaneous manifestations that may be painful, intensely pruritic, and disfiguring. Patients with LPL / WM have an overproduction of immunoglobulin (Ig) M-producing plasma cells and may develop plasma hyperviscosity due to the presence of this circulating monoclonal IgM protein (M protein). For patients with ALL or AML, the disruption of normal bone marrow function by an expanding clone of leukemic blasts leaves them prone to life-threatening infections and bleeding.

[005] Treatments for these diseases aim to induce tumor regression, slow tumor progression, control disease-related complications, and prolong life. Patients generally receive chemotherapeutic and / or immunotherapeutic agents. First-line therapies can provide lasting remissions. However, many patients will eventually experience disease recurrence; additional sequential therapies are used to try to control disease manifestations. Despite the use of agents with different mechanisms of action, progressive tumor resistance frequently develops. Patients with multiple relapsing progressive disease have a poor prognosis and are prone to dying from cancer. Thus, new mechanisms of action are needed to safely offer new treatment options for patients with hematologic cancers that have become resistant to existing therapies.

[006] The receptor tyrosine kinase type 1 orphan receptor (ROR1) is a cell surface protein that mediates signals from its ligand, the secreted glycoprotein Wnt5a. Consistent with its role in influencing the fate of Petition 870260064342, dated 06 / 30 / 2026, page 15 / 120 3 / 85 stem cells during embryogenesis, ROR1 expression is observed in invasive malignant diseases that revert to an embryonic transcriptional program, but is not observed in normal adult tissues. ROR1, therefore, offers a favorable selectivity profile as a therapeutic target. ROR1 is commonly expressed in malignant cells of patients with hematologic cancer and is also present on the cell surfaces of multiple solid tumors, where it appears to be a marker for cancerous stem cells.

[007] In view of the high unmet medical need in many patients with hematologic and other cancers and the role of ROR1 in cancer, there is a need for new therapies that can improve outcomes for patients, including patients who do not respond to existing therapies, through ROR1 targeting. SUMMARY OF THE INVENTION

[008] The present invention relates to a method of treating a cancer patient using an immunoconjugate having the structure shown below: cr nh2 (Formula I) wherein Ab is an antibody that binds specifically to the human tyrosine kinase receptor type 1 orphan receptor (ROR1), wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 1 and 2, respectively; and wherein the immunoconjugate is administered to the patient at a dose of 0.25 to 4.00 mg / kg. As used in the present Petition 870260064342, dated 06 / 30 / 2026, page 16 / 120 4 / 85 invention, Formula I above is not intended to denote that each Ab can be conjugated to only one copy of the drug fraction shown in the formula. In some embodiments, the number or copy of the drug fraction per antibody (DAR) varies from 1 to 7, where each drug fraction is conjugated to the antibody by means of a ligand as shown in Formula I.

[009] In some embodiments, the immunoconjugate is administered (e.g., intravenously) according to a dosage regimen described in the present invention. The immunoconjugate may be administered, for example, at doses of 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, or 3.00 mg / kg. In certain embodiments, the immunoconjugate may be administered in repeated three-week cycles (e.g., on Day 1 or Days 1 and 8 per cycle). In certain embodiments, the immunoconjugate may be administered in repeated four-week cycles (e.g., on Days 1, 8, and 15 per cycle). In some embodiments, the number of cycles may total 3, 6, or more. In specific modalities, the immunoconjugate can be administered: weekly during the first three, four, six, or eight weeks and then every three weeks; or every three weeks during the first three, six, or nine weeks and then weekly.

[010] In some modalities, the immunoconjugate is administered to a patient with hematologic cancer, such as lymphoid malignancy. In certain modalities, the cancer is selected from the group consisting of CLL, SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL, WM, NHL T cells, ALL, and AML. In particular modalities, the patient has been previously treated for cancer and / or has cancer that is recurrent or refractory to treatment (e.g., one or more existing cancer treatments, such as all existing treatments).

[011] In some modalities, treatment with the immunoconjugate Petition 870260064342, dated 06 / 30 / 2026, page 17 / 120 5 / 85 induces tumor regression (e.g., results in complete tumor eradication); slows tumor progression; inhibits cancer metastasis; prevents cancer recurrence or residual disease; decreases the size of nodal or extranodal tumor masses; decreases the number of malignant cells in the bone marrow and peripheral blood; decreases malignant splenomegaly or hepatomegaly; improves cancer-related anemia, neutropenia, or thrombocytopenia; improves cutaneous manifestations; decreases the likelihood of hyperviscosity syndrome in patients with LPL / WM; improves disabling constitutional symptoms; and / or prolongs survival.

[012] The present invention also provides an immunoconjugate for use in the treatment of cancer in a patient in a method described in the present invention. Additionally, the present invention provides the use of an immunoconjugate for the manufacture of a medicament for the treatment of cancer in a patient in a method described in the present invention. BRIEF DESCRIPTION OF THE FIGURES

[013] FIG. 1 is a graph showing plasma concentration curves over time that document total plasma exposures of ADC-A (solid line) and MMAE (dashed line). C: Cycle. D: Day. LLQ: Lower limit of quantification.

[014] FIG. 2 is a set of graphs that demonstrates the involvement of ROR1 ADC-A in circulating leukemia cells (upper panels) and plasma concentrations of ADC-A and MMAE (lower panels) over time in two individuals with CLL. Individual 1: left. Individual 2: right.

[015] FIG. 3 is a graph showing the correlation of unoccupied ROR1 receptors with plasma ADC-A concentration.

[016] FIG. 4 is a graph representing pharmacokinetic simulations of Petition 870260064342, dated 06 / 30 / 2026, page 18 / 120 6 / 85 plasma concentrations of ADC-A over time with Q1 / 3W, Q2 / 3W and Q3 / 4W dosing regimens.

[017] FIG. 5 is a graph showing the best change in tumor dimensions by the initial dose of ADC-A. TE: too early to evaluate. PR: partial response. DETAILED DESCRIPTION OF THE INVENTION

[018] The present invention provides treatment regimens using an ROR1 immunoconjugate. These treatment regimens can be used to treat a variety of cancers, such as those expected to express ROR1. 1. Immunoconjugates

[019] An “antibody-drug conjugate” or “ADC” or “immunoconjugate” refers to an antibody molecule or an antigen-binding fragment thereof that is covalently or non-covalently linked, with or without a ligand, to one or more biologically active molecule(s). The present immunoconjugates comprise antibodies or fragments thereof that are specific for human ROR1 and therefore can serve as excellent targeting fractions for delivering the conjugated payloads to cells (e.g., ROR1-positive cells). In certain embodiments, an immunoconjugate used in a treatment regimen of the invention is an immunoconjugate described in WO 2018 / 237335.

[020] Below are shown the SEQ ID NOs for the amino acid sequences of the heavy and light chain complementarity-determining regions (HCDRs and LCDRs), variable heavy and light chain domains (VH and VL) and heavy and light chains (HC and LC) of an exemplary anti-ROR1 antibody used in the immunoconjugates described in the present invention. Table 1 Petition 870260064342, dated 06 / 30 / 2026, p. 19 / 120 7 / 85 HCDR1 HCDR2 HCDR3 VH HC LCDR1 LCDR2 LCDR3 VL LC 5 6 7 3 1 8 9 10 4 2

[021] In some embodiments, the antibody or antibody fragment in the immunoconjugate binds specifically to human ROR1 and its heavy and light chains, respectively, comprise: a) the amino acid sequences HCDR1-3 in SEQ.ID NO: 1, and the amino acid sequences LCDR1-3 in SEQ ID NO: 2; b) HCDR1-3 comprising amino acid sequences SEQ ID NO: 5-7, respectively, and LCDR1-3 comprising amino acid sequences SEQ ID NOs: 8-10, respectively; c) HCDR1-3 comprising residues 26-33, 51-58 and 97-105 of SEQ ID NO: 3, respectively, and LCDR1-3 comprising residues 27-32, 5052 and 89-97 of SEQ ID NO: 4, respectively; d) HCDR1-3 comprising residues 26-32, 52-57 and 99-105 of SEQ ID NO: 3, respectively, and LCDR1-3 comprising residues 24-34, 5056 and 89-97 of SEQ ID NO: 4, respectively; or e) HCDR1-3 comprising residues 31-35, 50-66 and 99-105 of SEQ ID NO: 3, respectively, and LCDR1-3 comprising residues 24-34, 50-56 and 89-97 of SEQ ID NO: 4, respectively.

[022] In certain embodiments of an immunoconjugate described in the present invention, the antibody may be conjugated to the cytotoxic agent by means of a ligand. In some embodiments, the ligand is a cleavable ligand. A cleavable ligand refers to a ligand comprising a cleavable moiety and is typically susceptible to cleavage under in vivo conditions. In exemplary embodiments, the ligand may comprise a dipeptide, such as a valine-citrulline (val-citrulline VC) ligand. In certain embodiments, the ligand is linked to a cysteine ​​residue in the antibody. Petition 870260064342, dated 06 / 30 / 2026, p. 20 / 120 8 / 85

[023] In some embodiments, the conjugation of the ligand / payload to the antibody or fragment can be formed by reaction with a maleimide group (which may also be referred to as a maleimide spacer). In certain embodiments, the maleimide group is maleimidocaproyl (mc); thus, the ligand / payload is conjugated to the antibody or fragment by reaction between a residue in the antibody or fragment and the mc group in the ligand precursor.

[024] In some embodiments, the linker may include a benzoic acid or benzyloxy group or a derivative thereof. In some embodiments, the linker includes a para-amino-benzyloxycarbonyl (PAB) group.

[025] In some embodiments, the linkage between Ab and the payload or drug components (D) of the immunoconjugate can be formed by reacting the components with a ligand comprising a maleimide group, a peptide moiety and / or a benzoic acid group (e.g., PAB), in any combination. In certain embodiments, the maleimide group is maleimidocaproyl (mc). In certain embodiments, the peptide group is Val-Cit (VC). In certain embodiments, the ligand comprises a Val-CitPAB group. In certain embodiments, the conjugation of the ligand to the antibody or fragment can be formed from an mc-Val-Cit group. In certain embodiments, the linkage between the antibody or fragment and the drug moiety can be formed from an mc-Val-Cit-PAB group.

[026] The ligands can be conjugated to anti-ROR1 antibodies and antigen-binding fragments of the present invention in multiple ways. Generally, a ligand and a cytotoxic fraction are synthesized and conjugated before binding to an antibody. One method of linking a ligand-drug conjugate to an antibody involves solvent-exposed disulfide reduction with dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP), followed by Petition 870260064342, dated 06 / 30 / 2026, p. 21 / 120 9 / 85 modification of the resulting thiols with maleimide-containing drug-linker fractions (e.g., 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-VC-PAB)). A native antibody contains 4 interchain disulfide bonds and 12 intrachain disulfide bonds, as well as unpaired cysteines. Thus, antibodies modified in this way may comprise more than one drug-linker fraction per antibody. In certain embodiments, each of the immunoconjugates comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 drug / linker fractions. In certain embodiments, each of the immunoconjugates comprises one or more (e.g., 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2) ligand / drug fractions. In cases where the ligand is branched and each can bind to multiple drug fractions, the drug-to-antibody ratio will be higher than when using an unbranched ligand.

[027] In some embodiments, a cytotoxic agent suitable for use in an immunoconjugate described in the present invention may be, for example, an anti-tubulin agent, such as an auristatin. In certain embodiments, the cytotoxic agent is monomethyl auristatin E (MMAE).

[028] In some embodiments, an immunoconjugate described in the present invention is constructed as follows. Table 2 mAb Conjugation Ligand Components Payload Anti-ROR1 Antibody MAL (mc) VC PAB MMAE *MAL: maleimide chemistry (MAL).

[029] The anti-ROR1 antibody may be an anti-ROR1 antibody described in the present invention, for example, an antibody with a heavy chain amino acid sequence of SEQ ID NO: 1 and an amino acid sequence Petition 870260064342, dated 06 / 30 / 2026, p. 22 / 120 10 / 85 light chain SEQ ID NO: 2.

[030] In particular embodiments, an immunoconjugate used in the treatment regimens of the invention has the following structure (I): nh2 OH

[031] In some embodiments, the antibody is Ab1, which has a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2 (Ab1); this immunoconjugate may have a DAR of 3-6 and is referred to in the present invention as ADC-A. See also WO 2018 / 237335. The payload is conjugated to Ab1 via cysteine ​​residue(s) in the antibody polypeptide chains. 2. TREATMENT REGIMES

[032] In some embodiments, an ROR1 immunoconjugate described in the present invention (e.g., ADC-A) is administered at a dose of 0.25 to 10 mg / kg, for example, 0.25 to 4 mg / kg. For example, the immunoconjugate may be administered at a dose of 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 8, 9 or 10 mg / kg, or any combination thereof for multiple doses. In certain modalities, the immunoconjugate is administered in a dose of 0.50, 0.75, 1.00, 1.25, 1.50, Petition 870260064342, dated 06 / 30 / 2026, page 23 / 120 11 / 85 1.75, 2.00, 2.25, 2.50, 2.75 or 3.00 mg / kg.

[033] In some embodiments, the immunoconjugate is administered in repeated cycles of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In certain embodiments, the immunoconjugate is administered in three-week cycles. In certain embodiments, the immunoconjugate is administered in four-week cycles. The treatment regimen may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more administration cycles (e.g., 3 or more cycles, or 4 or more cycles). In certain embodiments, the immunoconjugate is administered on one, two, three, four, five, six, or seven days of the cycle. The administration days may be consecutive or may be one, two, three, four, five, or six days, one week, two weeks, three weeks, or four weeks, or any combination thereof. In particular modalities, the immunoconjugate is administered only on Day 1 of each cycle (e.g., a three-week cycle).In particular modalities, the immunoconjugate is administered on Days 1 and 8 of each cycle (e.g., a three-week cycle). In particular modalities, the immunoconjugate is administered on Days 1, 8, and 15 of each cycle (e.g., a four-week cycle).

[034] The immunoconjugate may be administered initially according to a dosing regimen described in this invention and then according to a different dosing regimen described in this invention (for example, to increase or decrease the frequency of administration). In some embodiments, the immunoconjugate is administered weekly during the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks and then every 3 weeks thereafter. In certain embodiments, the immunoconjugate is administered weekly during the first 2, 3, 4, 5 or 6 weeks and then every 3 weeks. In certain embodiments, the immunoconjugate is Petition 870260064342, dated 06 / 30 / 2026, p. 24 / 120 12 / 85 administered weekly for the first 1, 2, 3, 4, 5, or 6 weeks, and then every 4 weeks. The immunoconjugate can be administered, for example: - weekly for the first three weeks and then every three weeks; - weekly for the first four weeks and then every three weeks; - weekly for the first six weeks and then every three weeks; - weekly for the first eight weeks and then every three weeks; - every three weeks for the first three weeks and then weekly; - every three weeks for the first six weeks and then weekly; or - every three weeks for the first nine weeks and then weekly.

[035] In some embodiments, a dosing regimen described in the present invention achieves a plasma Cmax of the immunoconjugate of at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 pg / mL in the patient. In some embodiments, a dosing regimen described in the present invention achieves a plasma area under the concentration-time curve (AUC) of immunoconjugate of at least 500, 750, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250, or 3500 hours · μg / mL in the patient.

[036] In some embodiments, a dosing regimen described in the present invention maintains ROR1 receptor immunoconjugate occupancy of at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% in the patient. In some embodiments, a dosing regimen described in the present invention maintains at least 50% ROR1 receptor immunoconjugate occupancy for at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the time. In some embodiments, a dosing regimen described in the present invention maintains Petition 870260064342, dated 06 / 30 / 2026, p. 25 / 120 13 / 85 at least 75% immunoconjugate occupancy of the ROR1 receptor for at least 20, 30, 40, 50, 60, 70, 80 or 90% of the time. In some embodiments, a dosing regimen described in the present invention maintains at least 90% immunoconjugate occupancy of the ROR1 receptor for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5% of the time.

[037] The immunoconjugate can be administered via parenteral administration. As used in the present invention, “parenteral administration” of an immunoconjugate includes any route of administration characterized by the physical disruption of an individual’s tissue and administration of the immunoconjugate through the disruption in the tissue, thus generally resulting in direct administration into the bloodstream, muscle, or an internal organ. Parenteral administration, therefore, includes, but is not limited to, administration of an immunoconjugate by injection of the immunoconjugate, by application of the immunoconjugate through a surgical incision, by application of the immunoconjugate through a non-surgical wound that penetrates the tissue, and the like.In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intra-arterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intratumoral, and intrasynovial injections or infusions; and renal dialysis infusion techniques. Regional perfusion is also contemplated. In some modalities, the infusion may be administered via one route (e.g., intravenously) for initial doses and then via another route for subsequent doses.

[038] In certain embodiments, the immunoconjugate is administered by intravenous (IV) infusion. The IV infusion may occur over a period of approximately 0.1 to approximately 4 hours (e.g., approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, or 180). In particular embodiments, the Petition 870260064342, dated 06 / 30 / 2026, p. 26 / 120 14 / 85 The infusion time is 30 minutes. Infusion times may be extended as needed to accommodate the patient's individual treatment tolerance. When the immunoconjugate is administered in more than one dose, in some modalities, the infusion time for the first dose is longer than the infusion time for subsequent doses or, alternatively, the infusion time for the first dose is shorter than the infusion time for subsequent doses.

[039] In some modalities, the immunoconjugate is administered as monotherapy.

[040] It is understood that the treatment regimens of the invention may be treatment methods as described in the present invention, an immunoconjugate as described in the present invention for use in a treatment regimen described in the present invention, or use of an immunoconjugate as described in the present invention for the manufacture of a medicament for use in a treatment regimen described in the present invention. 3. PATIENT SELECTION

[041] The treatment regimens of the invention can be used to treat a cancer patient. In some embodiments, a treatment regimen of the invention includes the step of selecting a cancer patient described in the present invention. In certain embodiments, the patient may have been previously treated for said cancer and / or have cancer that is recurrent or refractory to one or more (or all) existing treatments for said cancer.

[042] Treat, treats and treatment refer to a method for alleviating or eliminating a biological disorder and / or at least one of its concomitant symptoms. As used in the present invention, relieving a disease, Petition 870260064342, dated 06 / 30 / 2026, page 27 / 120 15 / 85 disorder or condition means reducing the severity and / or frequency of occurrence of the symptoms of the disease, disorder or condition. Furthermore, references in the present invention to treatment include references to curative, palliative and prophylactic treatment. Cancer treatment encompasses inhibiting cancer growth (including causing partial or complete cancer regression), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and / or prolonging patient survival.

[043] In some embodiments, the patient to be treated with a treatment regimen of the invention has a cancer that expresses ROR1. Cancer that expresses ROR1 can be determined by any suitable method for determining gene or protein expression, for example, by histology, flow cytometry, radiopharmaceutical methods, RT-PCR, or RNA-Seq. The cancer cells used for the determination can be obtained through tumor biopsy or through the collection of circulating tumor cells. In certain embodiments, if an antibody-based assay, such as flow cytometry or immunohistochemistry, is used, cancers that express ROR1 are any cancers with cells that show anti-ROR1 antibody reactivity greater than that of a control antibody isotype.In certain modalities, if an RNA-based assay is used, cancers that express ROR1 are those that show an elevated level of ROR1 RNA compared to a negative control cell or cancer that does not express ROR1.

[044] In certain modalities, the patient has a hematological malignancy, such as a lymphoid malignancy. In certain modalities, the patient has a solid tumor. The patient may have a cancer selected from, for example, lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), marginal cell B-cell lymphoma, Burkitt lymphoma (BL), lymphoma of Petition 870260064342, dated 06 / 30 / 2026, page 28 / 120 16 / 85 mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), a non-Hodgkin lymphoma that has undergone Richter transformation, T-cell leukemia, T-cell lymphoma (e.g., T-cell non-Hodgkin lymphoma), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia (WM), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), hairy cell leukemia (HCL), myeloma, multiple myeloma (MM), sarcoma (e.g., osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, soft tissue sarcoma, or uterine sarcoma), brain cancer, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, neuroblastoma, head and neck cancer, nasopharyngeal cancer, thyroid cancer, breast cancer (by For example, ER / PR-positive breast cancer, HER2-positive breast cancer, or triple-negative breast cancer), lung cancer (for example, non-small cell lung cancer or small cell lung cancer),Malignant mesothelioma, bile duct / gallbladder cancer (e.g., cholangiocarcinoma), colon cancer, colorectal cancer, esophageal cancer, stomach cancer, gastric cancer, gastrointestinal stromal tumors (GISTs), liver cancer (hepatocellular), pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, epithelial squamous cell carcinoma, melanoma, adrenocortical carcinoma, gastrointestinal carcinoid tumors, islet cell tumors, pancreatic neuroendocrine tumors, neuroendocrine carcinoma of the skin (Merkel cell carcinoma), and pheochromocytoma. In certain modalities, the patient has cancer that is refractory to other therapies (e.g., triple-negative breast cancer).

[045] In particular modalities, the patient has a cancer selected from CLL / SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL / WM, cells Petition 870260064342, dated 06 / 30 / 2026, page 29 / 120 17 / 85 In NHL, ALL, and AML, the patient may have been previously treated for the cancer in question and / or have a cancer that is recurrent or refractory to one or more (e.g., all) existing treatments for the cancer in question.

[046] In some modalities, the patient is treatment-resistant or relapses with ibrutinib, acalabrutinib, autologous hematopoietic stem cell transplantation, bendamustine, bortezomib, brentuximab vedotin, carmustine, chimeric antigen receptor T-cell (CAR-T) therapy, cisplatin, copanlisib, cyclophosphamide, cytarabine, daratumumab, dexamethasone, doxorubicin, etoposide, gemcitabine, idelalisib, lenalidomide, melphalan, methotrexate, methylprednisolone, mosunetuzumab, obinutuzumab, ofatumumab, oxaliplatin, pinatuzumab, polatuzumab, rituximab, prednisone, radiotherapy, venetoclax, vincristine, or any combination thereof (e.g., any combination of previous treatment agents found in the Examples).

[047] In some modalities, the treatment regimen is administered to a human patient, for example, an adult patient (>18 years of age), an adolescent patient (>12 to 17 years of age), or a pediatric patient (<18 years of age) with adequate organ function and performance status who (i) has an advanced hematologic cancer or histologically confirmed solid tumor; and / or (ii) has a malignancy that is unlikely to respond to established therapies that provide clinical benefit, or has developed intolerance to established therapies that provide clinical benefit. In certain modalities, the patient meets both criteria. 4. TREATMENT RESULTS

[048] In some modalities, treatment with the immunoconjugate results in one or more of the following: Petition 870260064342, dated 06 / 30 / 2026, page 30 / 120 18 / 85 - induces partial or complete tumor regression, which in some cases can be maintained beyond the final treatment dose; - slows tumor progression (for example, by inhibiting tumor growth); - prevents cancer recurrence or residual disease; - reduces the size of nodal or extranodal tumor masses (which can be painful, disfiguring, or compressive); - It reduces the number of malignant cells in the bone marrow and peripheral blood; - reduces hepatomegaly or malignant splenomegaly; - improves cancer-related anemia, neutropenia, or thrombocytopenia (which can put patients at risk of fatigue, infection, or bleeding, respectively); - It alleviates skin manifestations (which can be painful, intensely itchy, or disfiguring); - reduces the likelihood of hyperviscosity syndrome in patients with LPL / WM; - alleviates debilitating constitutional symptoms; and - It prolongs survival.

[049] Treatment may result in any combination of the above results.

[050] In some embodiments, a treatment regimen of the invention reduces tumor dimensions in a patient by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the sum of the products of the perpendicular diameters (SPD). In some embodiments, a treatment regimen of the invention reduces tumor dimensions in a patient by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the Petition 870260064342, dated 06 / 30 / 2026, page 31 / 120 19 / 85 sum of the longest diameters of the target lesions. In some modalities, a treatment regimen of the invention completely eradicates the tumor.

[051] In some embodiments, a treatment regime of the invention (for example, to treat CLL and / or SLL) results in one or more (for example, any one, two, three, four, five, six or seven) of the following: a) no evidence of new disease; b) absolute lymphocyte count (ALC) in peripheral blood of <4 χ 109 / L; c) regression of all index nodal masses to <15 mm at the largest diameter (LD); d) normal spleen size of <120 mm per image in its longest vertical dimension (LVD) and normal liver size of <180 mm per image in its LVD; e) regression to normal (e.g., less than < 15 mm) of all non-nodal index diseases and disappearance of all detectable non-nodal index diseases; f) Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid cells and no lymphoid nodules in a normal-cellular bone marrow sample for age; and g) Peripheral blood meeting all of the following criteria: i) absolute neutrophil count (ANC) >1.5 x 10⁹ / L without exogenous growth factors <2 weeks prior to the relevant blood count assessment; ii) platelet count >100 x 10⁹ / L without exogenous growth factors or platelet transfusions <2 weeks prior to the relevant blood count assessment; and iii) hemoglobin >110 g / L (11.0 g / dL) without exogenous growth factors or red blood cell transfusions <2 weeks prior to the assessment. Petition 870260064342, dated 06 / 30 / 2026, page 32 / 120 20 / 85 relevant blood count.

[052] In certain embodiments, the treatment regimen results in all of a)–g) (“complete response”) and may additionally result in bone marrow aspirate flow cytometry showing malignant cells of <1x10–4 (“complete response without measurable residual disease”). In some embodiments, a treatment regimen of the invention results in one or more of the following (“complete response with incomplete count recovery”): a) a) af), g) (ii) eg) (iii), and absolute neutrophil count (ANC) <1.5 x 109 / L or requires exogenous growth factors <2 weeks before the relevant blood count assessment to maintain an ANC >1.5x109 / L; b) a) af), g) (i), eg) (iii), and platelet count <100 x 109 / L or requires exogenous growth factors or platelet transfusions <2 weeks before the relevant blood count evaluation to maintain a platelet count >100 x 109 / L; and c) a) af), g) (i), eg) (ii), and hemoglobin <110 g / L (11.0 g / dL) or requires exogenous growth factors or red blood cell transfusions <2 weeks before the relevant blood count assessment to maintain a hemoglobin >110 g / L (11.0 g / dL).

[053] In some embodiments, a treatment regime of the invention (for example, to treat CLL / SLL) results in one or more (for example, any one, two, three or four) of the following: a) no evidence of new disease; b) a change in disease status meeting two or more of the following criteria, except that if only lymphadenopathy is present at screening, only the lymphadenopathy must improve to the extent specified below: i) decrease in the absolute peripheral blood lymphocyte count (ALC) Petition 870260064342, dated 06 / 30 / 2026, p. 33 / 120 21 / 85 in >50% of screening; ii) a decrease of >50% from screening in the sum of the diameter products (SDP) of the nodal index lesions; iii) in an individual with splenic enlargement at screening, a decrease of >50% from screening (minimum decrease of 20 mm) in splenic enlargement in its longest vertical dimension (LVD) or to <120 mm by imaging; iv) in an individual with liver enlargement at screening, a decrease of >50% from screening (minimum decrease of 20 mm) in liver enlargement in its LVD or to <180 mm by imaging; and v) a decrease of >50% from screening in CLL / SLL bone marrow infiltrate or in B lymphoid nodules; c) no index, splenic, hepatic or non-index disease with worsening that meets the criteria for definite progressive disease (DP); and d) peripheral blood meeting one or more of the following criteria: i) absolute neutrophil count (ANC) >1.5 x 109 / L or an increase of >50% compared to screening without exogenous growth factors <2 weeks before the relevant blood count assessment; ii) platelet count >100 x 109 / L or an increase of >50% compared to screening without exogenous growth factors or platelet transfusions <2 weeks before the relevant blood count assessment; and iii) hemoglobin >110 g / L (11.0 g / dL) or an increase of >50% compared to screening without exogenous growth factors or red blood cell transfusions <2 weeks before the relevant blood count assessment.

[054] In certain modalities, the treatment regimen results in all of a) ad) (partial response). In certain modalities, the treatment regimen Petition 870260064342, dated 06 / 30 / 2026, page 34 / 120 22 / 85 results in all of a), b) ii) ab) v), c) ed) (partial response with lymphocytosis).

[055] In some embodiments, a treatment regime of the invention (for example, to treat CLL / SLL) results in one or both of the following: a) no evidence of new disease; and b) no evidence of tumor growth.

[056] In certain modalities, the treatment regimen results in a) and b) (stable disease”).

[057] In some embodiments, a treatment regimen of the invention (for example, to treat CLL / SLL) does not result in any of the following (which are signs of progressive disease): a) evidence of any new disease, as determined by one or more of: i) a new nodule measuring >15 mm in any diameter; ii) a splenic LVD >140 mm on imaging in individuals with a normal splenic LVD of <120 mm on imaging at nadir; iii) a liver LVD >200 mm on imaging in individuals with a normal liver LVD of <180 mm on imaging at nadir; iv) new effusions, ascites, or other histologically confirmed organ abnormalities related to CLL / SLL; v) a new extranodal lesion >10 mm; vi) new foci avid for fluorodeoxyglucose (FDG) consistent with lymphoma rather than another etiology (e.g., infection or inflammation); and vii) new or recurrent bone marrow involvement with lymphoma by PET or bone marrow biopsy if previous PET or bone marrow biopsy was negative for lymphoma; b) evidence of worsening of index lesions, spleen or liver, or non-index disease, as determined by one or more of: Petition 870260064342, dated 06 / 30 / 2026, page 35 / 120 23 / 85 i) increase from the nadir by >50% from the nadir in the sum of the products of the diameters (SPD) of the index lesions; ii) an increase from the nadir of >50% in the longest diameter (LD) of an individual nodule or extranodal mass that now has an LD of >15 mm and a LPD of >10 mm; iii) an increase in splenic enlargement of >50% (minimum increase of 20 mm) from the nadir in individuals with splenomegaly at screening or at the longest vertical dimension (LVD) splenic nadir; iv) an increase in liver enlargement of >50% (minimum increase of 20 mm) from the nadir in individuals with hepatomegaly at screening or at the nadir of hepatic LVD; v) unequivocal increase in the size of effusions, ascites, or other organ abnormalities related to CLL / SLL; and vi) transformation into a more aggressive histology, as established by lymph node biopsy; vii) a decrease in platelet or hemoglobin count that is attributable to CLL / SLL, is not attributable to an autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of clonal CLL / SLL cells, in which A) The current platelet count is <100 x 109 / L and there has been a decrease of >50% from baseline; and B) Current hemoglobin is <110 g / L (11.0 g / dL) and there has been a decrease of >20 g / L (2 g / dL) from baseline.

[058] In certain modalities, treatment does not result in any of the above results.

[059] In some embodiments, a treatment regimen of the invention (for example, to treat lymphoma) results in one or more (for example, any Petition 870260064342, dated 06 / 30 / 2026, page 36 / 120 24 / 85 one, two, three, four, five, six, seven or eight) of the following: a) no evidence of new disease; b) regression of all nodal index lesions to <15 mm in the LDi; c) regression to <15 mm of all non-index nodal diseases; d) disappearance of all detectable extranodal index and non-index diseases; e) normal spleen size of <130 mm per image in its longest vertical dimension (LVD); f) If PET is performed, no evidence of residual disease - that is, a score of 1 (no uptake above the antecedent), 2 (uptake < mediastinum) or 3 (uptake > mediastinum, but < liver) on the 5-point Deauville scale; g) negative for bone marrow involvement by PET for a PET-avid tumor or by morphological evaluation of a unilateral fragment biopsy; if the bone marrow biopsy is indeterminate by morphology, it must be negative by immunohistochemistry; and h) absence of serum M protein by SIFE (in individuals with LPL / WM).

[060] In certain modalities, the treatment regimen results in either a) ag) (complete response) or a) ah) (complete response in individuals with LPL / WM) and may additionally result in bone marrow aspirate flow cytometry showing malignant cells of <1χ10'4 (complete response without measurable residual disease). In certain modalities, the treatment regimen results in either a) ah), as well as a >90% decrease from baseline in serum protein M concentration.

[061] In some embodiments, a treatment regimen of the invention (for example, to treat lymphoma) results in one or more (for example, any one, two, three or four) of the following: Petition 870260064342, dated 06 / 30 / 2026, p. 37 / 120 25 / 85 a) no evidence of new disease; b) a decrease of >50% in the screening of nodal and extranodal index lesions in the SPD; c) no increase from the nadir in the size of the non-index disease; d) in an individual with splenic enlargement on screening, a decrease of >50% from screening (minimum decrease of 20 mm) in splenic enlargement in its longest vertical dimension (LVD) or to <130 mm per image; e) if PET is performed: i) Typically FDG-avid lymphoma: If no screening PET scan was performed or if the PET scan was positive before therapy, the treatment PET is positive in >1 previously involved site - i.e., a score of 4 (moderate uptake >liver) or a score of 5 (significant uptake >liver) on the 5-point Deauville scale, but with reduced uptake compared to screening. If a screening PET was performed and was negative, there is no new PET evidence of disease. Reduced uptake is defined as a >25% decrease in %ΔSUVmax; ii) variably FDG-avid lymphoma / unknown FDG avidity: if no pre-treatment PET scan was performed or if the pre-treatment PET scan was negative for lymphoma, CT criteria should be used in evaluating the tumor during treatment. If the PET scan is positive before therapy, the PET scan during treatment is positive in >1 previously involved site; f) persistence of bone marrow involvement in an individual who meets the radiographic criteria for complete response (CR); and g) a decrease of >50%, but <90% from baseline in serum protein M concentration (in individuals with LPL / WM). Petition 870260064342, dated 06 / 30 / 2026, page 38 / 120 26 / 85

[062] In certain modalities, the treatment regimen results in all of a) af) (“partial response”) or a) ag) (“partial response” in individuals with LPL / WM). In certain modalities, the treatment regimen results in all of a) af), as well as a decrease of >25%, but <50% from baseline in serum protein M concentration (“minor response” in LPL / WM).

[063] In some embodiments, a treatment regimen of the invention (for example, to treat lymphoma) results in one or more of the following:

[064] a) no evidence of new disease;

[065] b) no evidence of tumor growth; and

[066] c) a decrease <25% and an increase <25% from baseline in serum protein M concentration (in individuals with LPL / WM).

[067] In certain embodiments, a treatment regimen of the invention results in a) and b) (“stable disease”) or a) ac) (“stable disease” in individuals with LPL / WM). In certain embodiments, a treatment regimen of the invention results in a) and b), as well as a decrease of >25% but <50% from baseline in serum protein M concentration (“minor response” in LPL / WM).

[068] In some embodiments, a treatment regimen of the invention does not result in one or more of the following (which are signs of “progressive disease”): a) evidence of any new disease, as determined by one or more of: i) a new nodule measuring >15 mm in any diameter; ii) reappearance of an extranodal lesion that was resolved (i.e., a product of perpendicular diameters (PPD) of 0 mm2 was previously assigned); iii) a new extranodal lesion >10 mm; iv) new non-index disease (e.g., effusions, ascites, or other Petition 870260064342, dated 06 / 30 / 2026, page 39 / 120 27 / 85 organ abnormalities) of any size unequivocally attributable to lymphoma (e.g., as confirmed by PET, biopsy, cytology, or other non-radiological tests); v) new FDG-avid foci consistent with lymphoma rather than another etiology (e.g., infection or inflammation; if there is uncertainty as to the etiology of new lesions, biopsy or interval scanning may be considered); and vi) new or recurrent bone marrow involvement with lymphoma by PET or bone marrow biopsy if previous PET or bone marrow biopsy performed as part of the study was negative for lymphoma; b) evidence of worsening of nodal or extranodal index lesions, as determined by one or more of the following: i) increase from the nadir by >50% from the nadir in the sum of the products of the diameters (SPD) of the index lesions; ii) evidence of worsening of individual index lymph nodes or nodal masses with an increase from the nadir of >50% in PPD for any individual node if the node now has a LD of >15 mm, an increase of >50% from the nadir PPD and an increase in LD or SD from the nadir of >5 mm for lesions measuring <20 mm (in LD or shorter dimension (SDi)) or >10 mm for lesions measuring >20 mm (in LD or SDi) iii) unequivocal increase in the size of the non-index disease; and iv) an increase in splenic magnification of >50% (minimum increase of 20 mm) from nadir in a patient with a splenic LVD of >130 mm on imaging at nadir, or a splenic LVD of >150 mm on imaging in a patient with a splenic LVD of <130 mm on imaging at nadir; c) transformation to a non-Hodgkin lymphoma (NHL) histology more Petition 870260064342, dated 06 / 30 / 2026, page 40 / 120 28 / 85 aggressive, as established by lymph node biopsy; d) If PET is performed, there is a score of 4 (moderate uptake >liver) or a score of 5 (significant uptake >liver) on the 5-point Deauville scale with an increase in uptake compared to the nadir along with an anatomical increase in lesion size consistent with progressive disease (PD). Increased uptake is defined as an increase of >50% in %ΔSUVmax; and e) An increase from the nadir of >25% in serum protein M concentration (in individuals with LPL / WM).

[069] In certain modalities, the treatment does not result in any of a) ad) or does not result in any of the above results.

[070] In some embodiments, a treatment regimen of the invention (for example, to treat acute lymphoblastic leukemia) results in one or more (for example, any one, two or three) of the following: a) Leukemic disease status meeting all of the following requirements: i) <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); ii) no blasts in peripheral blood; and iii) no extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass and no central nervous system involvement (i.e., achieving CNS-1 status (no blasts in cerebrospinal fluid))); b) Peripheral blood meeting all of the following requirements: i) ANC > 1.0 x 109 / L; ii) platelet count >100 x 109 / L; and c) any mediastinal enlargement shows complete resolution as Petition 870260064342, dated 06 / 30 / 2026, page 41 / 120 29 / 85 documented radiographically.

[071] In certain modalities, the treatment regimen results in all of a) ac) (“complete response”) and may additionally result in flow cytometry of a bone marrow aspirate showing malignant cells of <1 x 10 -4 (“complete response with no measurable residual disease”).

[072] In some embodiments, a treatment regimen of the invention (for example, to treat acute lymphoblastic leukemia) results in one or more (for example, any one, two or three) of the following: a) Leukemic disease status meeting all of the following requirements: i) <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); ii) no blasts in peripheral blood; and iii) no extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass and no central nervous system involvement (i.e., achieving CNS-1 status (no blasts in cerebrospinal fluid))); b) Peripheral blood meeting all of the following requirements: i) ANC <1.0 x 109 / L; ii) platelet count <100 x 109 / L; and c) any mediastinal enlargement regressed by >75% in the sum of the products of perpendicular diameters (SPD) as documented radiographically.

[073] In certain modalities, the treatment regimen results in all of a) ac) (“complete response with incomplete blood count recovery” and / or “complete response not confirmed”).

[074] In some embodiments, a treatment regime of the invention (by Petition 870260064342, dated 06 / 30 / 2026, page 42 / 120 30 / 85 (for example, to treat acute lymphoblastic leukemia) results in one or more (for example, any one, two, or three) of the following: a) Leukemic disease status meeting any of the following requirements: i) A decrease of >50% in bone marrow blasts to 5% to 25% (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); ii) no blasts in peripheral blood; and iii) no new or worsening extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass, and no central nervous system involvement (e.g., CNS-1 status (no blasts in cerebrospinal fluid) has not transitioned to CNS-2 status (WBC <5 x 109 / L with presence of blasts in cerebrospinal fluid) or to CNS-3 status (WBC >5 x 109 / L with presence of blasts in cerebrospinal fluid) or to the development of facial nerve paralysis, brain / eye involvement, or hypothalamic syndrome)); b) Peripheral blood meeting all of the following requirements: i) ANC >1.0 x 109 / L; ii) platelet count >100 x 109 / L; and c) any mediastinal enlargement regressed by >50% in the SPD as documented radiographically.

[075] In certain modalities, the treatment regimen results in all of a) ac) (“partial response”).

[076] In some embodiments, a treatment regimen of the invention (for example, to treat acute lymphoblastic leukemia) results in one or more (for example, one, two or three) of the following: Petition 870260064342, dated 06 / 30 / 2026, p. 43 / 120 31 / 85 a) neither sufficient improvement in ALL from baseline to qualify for PR nor sufficient evidence of worsening ALL to qualify for DRP; b) no new or worsening extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass and no central nervous system involvement (e.g., CNS-1 status (no blasts in cerebrospinal fluid) has not transitioned to CNS-2 status (WBC <5 x 109 / L with presence of blasts in cerebrospinal fluid) or to CNS-3 status (WBC >5 x 109 / L with presence of blasts in cerebrospinal fluid) or to the development of facial nerve paralysis, brain / eye involvement or hypothalamic syndrome)); c) no development of new mediastinal enlargement and no increase in SPD of existing mediastinal enlargement by >25%.

[077] In certain embodiments, a treatment regimen of the invention results in all of a) ac) (stable disease”).

[078] In some embodiments, a treatment regimen of the invention (for example, to treat acute lymphoblastic leukemia) does not result in one or more (for example, one, two, three, four, five or six) of the following (which are signs of disease recurrence or progression, DRP”): a) reappearance of bone marrow blasts (for >5%) in an individual who has experienced a CR; b) reappearance of blasts in the peripheral blood of an individual who has experienced a CR; c) an increase >25% in bone marrow blasts to >20% (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); Petition 870260064342, dated 06 / 30 / 2026, p. 44 / 120 32 / 85 d) an increase of >25% in blasts in peripheral blood to >1 x 109 / L; and e) development of new or worsened existing extramedullary disease (involving lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass, or CNS involvement (e.g., CNS-1 state (no blasts in cerebrospinal fluid) transitioned to CNS-2 state (WBC <5 x 109 / L with presence of blasts in cerebrospinal fluid) or CNS-3 state (WBC >5 x 109 / L with presence of blasts in cerebrospinal fluid) or to the development of facial nerve paralysis, brain / eye involvement, or hypothalamic syndrome)); and f) development of new mediastinal enlargement or increase in the SPD of existing mediastinal enlargement by >25%.

[079] In certain modalities, the treatment does not result in any of a) af).

[080] In some embodiments, a treatment regimen of the invention (for example, to treat acute myeloid leukemia) results in one or both of the following: a) Leukemic disease status meeting all of the following requirements: i) <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); ii) no blasts in peripheral blood; iii) without blasts containing Auer rods; and iv. without extramedullary disease; and b) peripheral blood meeting both of the following requirements: i) ANC > 1.0 x 109 / L; ii) platelet count >100 x 109 / L.

[081] In certain modalities, the treatment regime results in a) and b) Petition 870260064342, dated 06 / 30 / 2026, p. 45 / 120 33 / 85 (“complete response”) and may additionally result in flow cytometry of a bone marrow aspirate showing malignant cells of <1 χ 10-4 (“complete response with no measurable residual disease”).

[082] In some embodiments, a treatment regimen of the invention (for example, to treat acute myeloid leukemia) results in one or both of the following: a) Leukemic disease status meeting all of the following requirements: i) <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); ii) no blasts in peripheral blood; iii) without blasts containing Auer rods; and iv) without extramedullary disease; and b) peripheral blood meeting only one of the following criteria: i) ANC >1.0 x 109 / L; and ii) platelet count >100 x 109 / L.

[083] In certain modalities, the treatment regimen results in a) and b) (“complete response with incomplete recovery of the blood count”).

[084] In some embodiments, a treatment regimen of the invention (for example, to treat acute myeloid leukemia) results in one or both of the following: a) Leukemic disease status meeting all of the following requirements: i) <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); ii) no blasts in peripheral blood; iii) without blasts with Auer rods; and Petition 870260064342, dated 06 / 30 / 2026, p. 46 / 120 34 / 85 iv) without extramedullary disease; and b) Peripheral blood meeting both of the following criteria: i) ANC <1.0 x 109 / L; and ii) platelet count <100 x 109 / L.

[085] In certain modalities, the treatment regimen results in a) and b) (“morphological leukemia-free state”).

[086] In some embodiments, a treatment regimen of the invention (for example, to treat acute myeloid leukemia) results in one or both of the following: a) Leukemic disease status meeting any of the following requirements: i) A decrease of >50% in bone marrow blasts to 5% to 25% (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); ii) <5% bone marrow blasts, but with the presence of Auer rods (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); iii) no blasts in the peripheral blood; and iv) no new or worsened extramedullary disease; and b) Peripheral blood meeting both of the following criteria: i) ANC >1.0 x 109 / L; and ii) platelet count >100 x 109 / L.

[087] In certain modalities, the treatment regimen results in a) and b) (“partial response”).

[088] In some embodiments, a treatment regimen of the invention (for example, to treat acute myeloid leukemia) results in one or both of the following: Petition 870260064342, dated 06 / 30 / 2026, p. 47 / 120 35 / 85 a) no sufficient improvement in AML from baseline to qualify for CRMrd-, CR, CRi, MLFS, or PR, nor sufficient evidence of worsening AML to qualify for DRP; and b) no new or worsened extramedullary disease.

[089] In certain embodiments, a treatment regimen of the invention results in a) and b) (stable disease).

[090] In some embodiments, a treatment regimen of the invention (for example, to treat acute myeloid leukemia) does not result in one or more of the following (which are signs of disease recurrence or progression, DRP): a) reappearance of bone marrow blasts (for >5%) in an individual who experienced CRMrd-, CR, CRi or MLFS; b) reappearance of blasts in the peripheral blood in an individual who has experienced CRMrd-, CR, CRi, MLFS or PR; c) an absolute increase of 20% in bone marrow blasts to >25% (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules) in an individual who presented with RP; d) an absolute increase of 20% in peripheral blasts to >25% in an individual who experienced a PR; and e) development of a new extramedullary disease or worsening of an existing extramedullary disease.

[091] In certain modalities, the treatment does not result in any of a) ae).

[092] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) results in one or both of the following: a) disappearance of all target lesions and no new measurable lesions (e.g., lesions that can be accurately measured in Petition 870260064342, dated 06 / 30 / 2026, p. 48 / 120 36 / 85 >1 dimension (largest diameter to be recorded) as >10 mm with CT scans with a minimum slice thickness of 5 mm) or caliper measurement of >10 mm by clinical examination, or >20 mm by chest X-ray); and b) reduction in the short axis to <10 mm for any pathological lymph nodes, target (e.g., >15 mm in the short axis when assessed by CT scan (minimum slice thickness of 5 mm)) or non-target (e.g., >10 mm, but <15 mm).

[093] In certain modalities, the treatment regimen results in a) and b) (“complete response” for target lesions).

[094] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) results in a >30% decrease in the sum of the diameters of the target lesions, taking as a reference the baseline sum of the diameters and including any new measurable lesions that may have appeared since baseline (“partial response” for target lesions).

[095] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) results in a >30% decrease in the sum of the diameters of the target lesions, taking as a reference the baseline sum of the diameters and including any new measurable lesions that may have appeared since baseline (“partial response” for target lesions).

[096] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) does not result in sufficient shrinkage to qualify for a partial response, taking as a reference the baseline sum of diameters, nor in sufficient increase to qualify for progressive disease, taking as a reference the smallest sum of diameters during treatment (“stable disease” for target lesions).

[097] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) does not result in an increase of >20% (and Petition 870260064342, dated 06 / 30 / 2026, p. 49 / 120 37 / 85 an absolute increase of >5 mm) in the sum of the diameters of the target lesions (including any new lesions), taking as a reference the smallest post-baseline sum (nadir tumor burden) or baseline sum if that is the smallest sum during treatment (“progressive disease” for target lesions).

[098] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) results in one or more of the following: a) disappearance of all non-target lesions; b) normalization of an elevated tumor marker level; and c) all lymph nodes are non-pathological in size (<10 mm in the short axis).

[099] In certain modalities, the treatment regimen results in all of a) ac) (“complete response” for non-target lesions). In certain modalities, the treatment regimen results in b) and c), but not in a), or a) and c), but not in b) (“incomplete response / non-progressive disease” for non-target lesions).

[100] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) does not result in unequivocal progression of existing non-target lesions (“progressive disease” for non-target lesions).

[101] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) results in an overall response of: - absence of target lesions and new measurable lesions; absence of non-target lesions or tumor markers; and absence of new unmeasurable lesions (“complete response”); - absence of target lesions and new measurable lesions; and stable non-target lesions or tumor markers (“partial response”); - absence of target lesions and new measurable lesions; and unequivocal progression in non-target lesions or tumor markers ("partial response"); - a decrease of >30% in target lesions and new measurable lesions; and Petition 870260064342, dated 06 / 30 / 2026, page 50 / 120 38 / 85 absent, stable, or unequivocal progression in non-target lesions or tumor markers (“partial response”); or - a decrease of <30% to an increase of <20% in target lesions and new measurable lesions; and absent, stable, or unequivocal progression in non-target lesions or tumor markers (“stable disease”).

[102] In some embodiments, a treatment regimen of the invention (for example, to treat a solid tumor) does not result in a >20% increase in target lesions and new measurable lesions; and absent, stable or unequivocal progression in non-target lesions or tumor markers (“progressive disease”).

[103] In some embodiments, a treatment regime of the invention results in one or more of the following results, for example, as defined above or in the Examples: - CLL / SLL: a CR, CRi, PR, or PR-L; - FL, MZL, MCL, DLBCL, or BL: a CR or PR; - LPL / WM: one CR, VGPR, PR or MR; - ALL: a CR, CRi / CRu or PR; - AML: a CR, CRi, or PR; or - Solid tumor: a CR or PR.

[104] In some embodiments, a treatment regimen of the invention does not result in one or more (for example, any one, two, three, four, five, six, seven, eight, nine or ten) of the following in the first treatment cycle: a) Grade >3 febrile neutropenia; b) Neutropenia of grade >4; c) Grade 3 thrombocytopenia with bleeding >3; d) Thrombocytopenia grade >4; e) Grade 3 tumor lysis syndrome (TLS) despite adequate prophylaxis that does not resolve within 72 hours of onset; Petition 870260064342, dated 06 / 30 / 2026, p. 51 / 120 39 / 85 f) TLS grade >4 despite adequate prophylaxis; g) Vomiting of grade >3 despite recommended (or equivalent) antiemetic support; h) Grade >3 non-hematological laboratory abnormalities that do not improve to Grade <1 or baseline within 72 hours; i) Other Grade >3 non-hematological treatment-emergent adverse events (TEAEs) (except for Grade 3 fatigue); and j) Failure to recover baseline for >21 days from the last dose of the immunoconjugate in the cycle due to a drug-related TEAE,

[105] wherein all degrees are defined using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. In certain embodiments, a treatment regimen of the invention does not result in any of the aforementioned outcomes.

[106] In some embodiments, a treatment regime of the invention does not result in one or more (for example, any one, two, three, four, five or six) of the following: a) any complication that occurs as a result of a procedure mandated by protocol (e.g., venipuncture, ECG); b) any pre-existing condition that increases in severity or changes in nature during or as a consequence of drug administration (e.g., worsening of underlying cancer manifestations, such as increased pain, exacerbated tumor reaction, TLS, etc.); c) any injury or accident; d) any abnormality in the physiological test or physical examination finding that requires clinical intervention or further investigation (beyond requesting a repeat or confirmatory test); e) any laboratory abnormality (e.g., clinical chemistry, Petition 870260064342, dated 06 / 30 / 2026, p. 52 / 120 40 / 85 hematology, urinalysis) or investigational (e.g., ECG, X-ray) independent of the underlying medical condition requiring clinical intervention, results in further investigation (beyond requesting a repeat or confirmatory test), or leads to interruption or discontinuation of the investigational medicinal product, unless it is associated with a previously reported clinical event; and f) a complication related to pregnancy or the termination of a pregnancy.

[107] In certain embodiments, a treatment regime of the invention does not result in any of the aforementioned results.

[108] In some embodiments, a treatment regime of the invention does not result in one or more (for example, any one, two, three, four, five or six) of the following: a) death; b) life-threatening situation with immediate risk of death; c) hospital admission or extension of existing hospitalization; d) persistent or significant disability / impairment; (e) congenital anomaly / birth defect in the children of an individual who received the immunoconjugate; and f) a clinically significant event that may not be immediately life-threatening or result in death or hospitalization, but based on sound medical and scientific judgment, may place the individual at risk or may require medical or surgical intervention to prevent one of the outcomes listed above (e.g., allergic bronchospasm requiring intensive treatment in an emergency room or at home, new cancers or blood dyscrasias, seizures that do not result in hospitalization, or development of drug dependence or drug abuse). Petition 870260064342, dated 06 / 30 / 2026, page 53 / 120 41 / 85

[109] In certain embodiments, a treatment regime of the invention does not result in any of the aforementioned results.

[110] In some embodiments, a treatment regime of the invention does not result in one or more (for example, one, two or three) of the following: a) Infusion reactions of grade >3; b) tumor lysis syndrome (TLS) of any grade; and c) Peripheral neuropathy of grade >3;

[111] where all grades are defined using Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

[112] In certain embodiments, a treatment regime of the invention does not result in any of the aforementioned results.

[113] In some embodiments, a treatment regimen of the invention does not result in abnormalities in one or more (for example, any one, two, three, four, five, six, seven, eight or nine) of the following: urine, serum, blood, systolic blood pressure, diastolic blood pressure, pulse, body temperature, blood oxygen saturation and electrocardiography (ECG) readings. In certain embodiments, a treatment regimen of the invention does not result in abnormalities of any of the foregoing.

[114] In some embodiments, a treatment regimen of the invention does not result in detectable levels of circulating immunoconjugate-reactive antibodies in the patient's serum.

[115] It is understood that the treatment regimens described in the present invention may be treatment methods as described in the present invention, an immunoconjugate as described in the present invention for use in a treatment regimen described in the present invention, or use of an immunoconjugate as described in the present invention for the manufacture of a medicament for a treatment regimen described in the present invention. Petition 870260064342, dated 06 / 30 / 2026, page 54 / 120 42 / 85 5. Pre-medications or simultaneous medications for tumor lysis syndrome prophylaxis

[116] In some embodiments, a patient to be treated with a treatment regimen of the invention is assessed for the risk of tumor lysis syndrome (TLS) using the following criteria:

[117] CLL / SLL and NHL: (i) Low risk: Serum lactate dehydrogenase (LDH) < upper limit of normal (ULN), all measurable lymph nodes <5 cm in diameter and ALC <25 x 109 / L. (ii) Intermediate risk: Serum LDH >1 to <2 x ULN, >1 measurable lymph node of >5 but <10 cm in diameter, or ALC >25 x 109 / L. (iii) High risk: serum LDH >2 x ULN, >1 measurable lymph node >10 cm in diameter, or both >1 measurable lymph node with an LD of >5, but <10 cm in diameter and ALC >25 x 109 / L.

[118] ALL: (i) Low risk: white blood cell count (WBC) <20 x 109 / L and serum LDH level <2 x ULN. (ii) Intermediate risk: WBC>20x 109 / L <100x 109 / L serum LDH level <2x ULN (iii) High risk: WBC >100 x 109 / L or serum LDH level >2 x ULN.

[119] AML: (i) Low risk: Serum LDH <2 x ULN, serum uric acid <5.5 mg / dL and WBC <25 x 109 / L. (ii) Intermediate risk: Serum LDH >2 x ULN, or serum uric acid >5.5 mg / dL and <7 mg / dL, or WBC >25 x 109 / L to <100 x 109 / L. (iii) High risk: Serum uric acid >7 mg / dL or WBC >100 x 109 / L.

[120] In some modalities, if a patient is at intermediate risk Petition 870260064342, dated 06 / 30 / 2026, page 55 / 120 If TLS is 43 / 85 or high and / or elevated during treatment, the patient may receive allopurinol and / or febuxostat before or during treatment. A patient with hyperuricemia may additionally receive rasburicase. For example, the patient may receive the aforementioned drug(s) according to a regimen described below: (i) Intermediate risk of TLS: The patient may receive allopurinol, 100 to 300 mg orally every 8 hours, starting >24 to 48 hours before the start of drug therapy; it is worth noting that the maximum daily dose of allopurinol is 800 mg, doses <300 mg do not need to be divided, and doses should be reduced by >50% in individuals with renal impairment. Alternative drugs (e.g., febuxostat) may be substituted, administered according to the product label. In addition, patients with hyperuricemia may receive rasburicase, 3 to 4.5 mg by IV infusion. (ii) High Risk of TLS: The patient may receive allopurinol, 100 to 300 mg orally every 8 hours, starting >24 to 48 hours before the start of drug therapy; it is worth noting that the maximum daily dose of allopurinol is 800 mg, doses <300 mg do not need to be divided (but may be insufficient for high-risk individuals), and doses should be reduced by >50% in individuals with renal impairment. Alternative drugs (e.g., febuxostat) may be substituted, administered according to the product label. In addition, high-risk patients may receive rasburicase, 3 to 4.5 mg by IV infusion, administered 3 to 4 hours before the first dose of the drug.

[121] In some modalities, patients are monitored for TLS during Cycle 1, Day 1 (C1D1) through C1D3 with assessments of vital signs, AEs, and laboratory studies of serum chemistry and hematology. Petition 870260064342, dated 06 / 30 / 2026, page 56 / 120 44 / 85 Infusion reaction prophylaxis

[122] In some embodiments, before or during receiving a treatment regimen of the invention, a patient may receive an antipyretic and / or an antihistamine to reduce the incidence and severity of infusion reactions. In certain embodiments, the antipyretic may be administered orally or IV and may be, for example, acetaminophen (paracetamol), 650 to 1,000 mg or equivalent. In certain embodiments, the antihistamine may be administered orally or IV and may be, for example, cetirizine, 10 mg or equivalent. In some embodiments, one or both medications are administered 30 to 60 minutes before each immunoconjugate infusion. A nonsteroidal anti-inflammatory drug (NSAID), such as ibuprofen, 400 to 800 mg orally or equivalent, may be added to or substituted for acetaminophen. A corticosteroid such as prednisolone, 100 mg or equivalent, may also be considered as a premedication. ANTIEMETIC PROPHYLAXIS

[123] In some embodiments, before or during receiving a treatment regimen of the invention, a patient may receive an antiemetic to treat nausea and / or vomiting. Neutropenia Management

[124] In some embodiments, before or during receiving a treatment regimen of the invention, a patient may receive G-CSF (e.g., filgrastim, frastim-SND, PEG-filgrastim or lenograstim) or GM-CSF (e.g., sargramostim) to prevent or mitigate drug-induced neutropenic complications and promote neutrophil recovery. MANAGEMENT OF HYPERVISCOSITY SYNDROME (HVS)

[125] HVS is a clinical feature in 10% to 30% of patients with LPL / WM due to the presence of high levels of circulating M protein. Therapy Petition 870260064342, dated 06 / 30 / 2026, page 57 / 120 Immediate treatment for symptomatic HVS is typically plasmapheresis. In some embodiments, prior to or during receiving a treatment regimen of the invention, a patient may receive plasmapheresis to prevent or mitigate HVS. 6. MANUFACTURING ARTICLES AND KITS

[126] The present invention also provides articles of manufacture, for example, kits, comprising one or more containers (for example, single-use or multi-use containers) containing a pharmaceutical composition of an immunoconjugate described in the present invention at a dose described in the present invention, optionally, an additional biologically active molecule (for example, another therapeutic agent) and instructions for use according to a treatment regimen described in the present invention. The immunoconjugate and the additional biologically active molecule may be packaged together or separately in suitable packaging, such as a vial or ampoule made of glass or non-reactive plastic. In some embodiments, the vial or ampoule contains a liquid containing the immunoconjugate or a lyophilized powder comprising the immunoconjugate; the liquid or lyophilized powder may optionally include the additional therapeutic agent or biologically active molecule.In certain embodiments, the vial or ampoule contains a concentrated stock (e.g., 2x, 5x, 10x or more) of the immunoconjugate and, optionally, the biologically active molecule. In particular embodiments, a pharmaceutical composition of an immunoconjugate described in the present invention (e.g., ADC-A) is packaged in a single-use glass vial containing 50 mg, 100 mg, 150 mg, 200 mg, 250 mg or 300 mg of the immunoconjugate (e.g., suitable for use at a dose described in the present invention, such as 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75 or 3.00 mg / kg). In certain embodiments, articles of manufacture, such as kits, include a medical device for administration. Petition 870260064342, dated 06 / 30 / 2026, page 58 / 120 46 / 85 the immunoconjugate and / or biologically active molecule (e.g., a syringe and a needle); and / or an appropriate diluent (e.g., sterile water and normal saline solution). The present invention also includes methods for manufacturing said articles.

[127] Unless the context requires otherwise, throughout the descriptive report and claims, the word "understand" and variations thereof, such as "understands" and "understanding," should be interpreted in an open and inclusive sense, that is, as including, but not limited to. As used in this descriptive report and the appended claims, the singular form of "a," "an," and "the" includes plural references, unless the context clearly indicates otherwise. It should also be noted that the term "or" is generally employed in its inclusive and / or sense, unless the content clearly indicates otherwise. As used in the present invention, the term "about" refers to a numerical range that is 10%, 5%, or 1% more or less of a stated numerical value within the context of the particular use. Furthermore, the headings provided in this invention are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

[128] All publications and patents mentioned in the present invention are incorporated into the present invention by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which may be used in connection with the inventions described herein. The publications discussed in the present invention are provided only for their disclosure prior to the filing date of this application. Nothing in this invention shall be construed as an admission that the inventors of the invention in question do not have the right to anticipate such disclosure by virtue of the prior invention or for any other reason. Petition 870260064342, dated 06 / 30 / 2026, p. 59 / 120 47 / 85

[129] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by a person skilled in the art to which the inventions described in the present invention pertain. Any methods, devices and materials similar or equivalent to those described in the present invention may be used in the practice or testing of the inventions described in the present invention. EXAMPLES

[130] The following examples illustrate representative embodiments of the present invention and are not intended to be limiting in any way. EXAMPLE 1: ADC-A SYNTHESIS

[131] The conjugation of Ab1 with MC-VC-PAB-MMAE (ADC-A) was performed on multiple scales (from 2 mg to 200 g) with similar results. On a large scale, approximately 200 g of Ab1 (approximately 40 mg / mL in 50 mM sodium citrate, 10 mg / mL trehalose, 0.05 mM EDTA, 0.02% polysorbate 80, pH 5.2) was treated with 1.90 equivalents (eq) of tris(2-carboxyethyl)phosphine (TCEP, 5 mM) and maintained at 20–24 °C for 330 minutes. Then, 6.5 eq of MC-VC-PAB-MMAE in N,N-dimethylacetamide (DMA) was added and the mixture was maintained at 22–23 °C for a further 60 minutes. The buffer was replaced with 10 mM sodium acetate, pH 4.8 by ultrafiltration / diafiltration (UF / DF) using 30 kD UF membrane cassettes. The number of MMAE drug molecules bound per antibody molecule (DAR) was determined using HIC-HPLC. HIC-HPLC, SEC-HPLC, RP-HPLC, and UV / Vis data are summarized in Table 3 below.Consistent results were obtained across all scales, with DAR ranging from 3.89 to 5.09 on average, depending on the methodology used. Table 3. Drug-ADC-Antibody Ratio (DAR) Petition 870260064342, dated 06 / 30 / 2026, page 60 / 120 48 / 85 Scale Aggregate (%) Recovery (%) D0* (%) DAR UV SEC HIC RP 2 mg 3.47 85.6 6.06 4.33 4.81 3.95 3.89 30 mg 3.50 86.1 4.75 4.44 5.09 4.21 4.09 350 mg 3.51 90.2 5.12 4.40 4.96 4.12 3.99 200 g 2.1 95.4 4.9 4.0 * D0: unconjugated antibody. EXAMPLE 2: DOSE INTENSIFICATION STUDY FOR Anti-ROR1-MMAE Immunoconjugates

[132] The following describes a protocol for evaluating the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy of an ROR1 immunoconjugate (ADC-A) across a range of dose levels when administered to individuals with previously treated relapsed or refractory CLL / SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL / WM, NHL, ALL, or AML T cells. ADC-A is administered intravenously (IV) in repeated 3-week cycles with a drug infusion on Day 1 of each cycle (Q1 / 3W [Schedule 1]); in repeated 3-week cycles with drug infusions on Days 1 and 8 of each cycle (Q2 / 3W [Schedule 2]); or in repeated 4-week cycles with drug infusions on Days 1, 8, and 15 of each cycle (Q3 / 4W [Schedule 3]) over a planned infusion time of ~30 minutes. Infusion times may be extended as needed to accommodate the individual's tolerance to treatment. Table 4. ADC-A dosage schedules Schedule Cycle Duration Dosage Days During Cycle Designation 1 3 weeks Day 1 Q1 / 3W 2 3 weeks Days 1 and 8 Q2 / 3W Petition 870260064342, dated 06 / 30 / 2026, p. 61 / 120 49 / 85 Schedule Cycle Duration Dosage Days During Cycle Assignment 3 4 weeks Days 1, 8 and 15 Q3 / 4W DOSE LEVELS

[133] The initial cohort of individuals will be prescribed ADC-A at 0.50 mg / kg Q1 / 3W. Subsequently, cohorts of individuals will be sequentially enrolled at progressively higher initial dose levels of ADC-A to be administered on Q1 / 3W, Q2 / 3W, or Q3 / 4W (Tables 4 and 5). An initial dose of 0.25 mg / kg may be administered on the Q1 / 3W schedule to allow for dose tapering if an individual experiences a TEAE requiring dose modifications to a level below the initial level. Table 5. ADC-A Dose Levels Q1 / 3W Q2 / 3W Q3 / 4W 0.50 1.00 1.50 2.25 2.50 2.75§ 3.00§ 0.75* 0.75* Initial level 1.00 Initial level 1.00 1.25 1.25 1.50 1.50 1.75 1.75 2.00 2.00 2.25 2.25 *The initial dose level is 1.00 mg / kg. The 0.75 mg / kg dose is provided to allow for a dose decrease if an individual experiences a treatment-emergent adverse event (TEAE) that requires dose modifications to a level below 1.00 mg / kg. § It can be administered if individuals tolerate ADC-A therapy at the previous dose level.

[134] Accelerated dose escalation in a single individual at the level Petition 870260064342, dated 06 / 30 / 2026, p. 62 / 120 A 50 / 85 initial dose using the Q1 / 3W schedule is planned. Subsequently, cohorts of 3 to 6 individuals will be sequentially enrolled, evaluating each administration schedule at progressively higher dose levels of ADC-A using a standard 3+3 dose escalation design. Based on the pattern of dose-limiting toxicities (DLTs) observed in Cycle 1, escalation will proceed to define a maximum tolerated dose (MTD) and a recommended dosing regimen (RDR) for each administration schedule, which may be at the MTD or a lower dose within the tolerable dose range. The MTD is the highest tested dose level at which >6 individuals were treated and which is associated with a dose-limiting toxicity (DLT) from Cycle 1 in <17% of individuals. The RDR may be the MTD or a lower dose within the tolerable dose range.The selection of each RDR will be based on consideration of short- and long-term safety information, along with available pharmacokinetic, pharmacodynamic, and efficacy data, and may be defined in the context of the level of supportive care (e.g., antiemetic or hematopoietic prophylaxis) provided to individuals to obtain the RDR. Once each RDR has been established, further development will be considered in specific hematologic cancers and / or solid tumors.

[135] ADC-A administered to patients according to the dosage regimens provided is expected to achieve the overall response (OR), defined as achieving the following outcomes by disease type: - CLL / SLL: Complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L); NHL: CR or PR; - LPL / WM: CR, very good partial response (VGPR), PR or lower response Petition 870260064342, dated 06 / 30 / 2026, page 63 / 120 51 / 85 (MR); - ALL: CR, CRi or unconfirmed complete response (CRu) (for individuals with mediastinal disease) or PR; and - AML: CR, CRi, morphologically leukemia-free state (MLFS) or PR.

[136] CR without measurable residual disease (CRmrd-) is defined as obtaining <1 χ 10-4 malignant cells in the bone marrow (as assessed by flow cytometry) in an individual who meets all other criteria for CR. ADC-A, when administered according to the dosing regimens provided in the present invention, is also expected to lead to improvements in percent change in tumor dimensions (defined as the percent change from baseline in the sum of products of diameters (SPD) of index lesions), progression-free survival (PFS) (defined as the interval from the start of study therapy to the onset of first documented disease progression / recurrence or death from any cause), and overall survival (OS) (defined as the interval from the start of study therapy to death from any cause).

[137] The ADC-A dosing regimen may also lead to changes (e.g., increase or decrease) in plasma Wnt5a concentrations (as assessed by immunoassay), changes (e.g., increase or decrease) in plasma circulating ROR1 concentrations (as assessed by immunoassay), and changes in the numbers (e.g., increase or decrease) or activation status (e.g., increase or decrease) of immune cells, such as circulating B cells, T cells, and natural killer (NK) cells. PATIENT SELECTION

[138] In the study, patients may be adult patients aged 18 years or older; were diagnosed with CLL / SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL / WM, NHL T-cells, ALL, or AML; had been previously treated but progressed Petition 870260064342, dated 06 / 30 / 2026, page 64 / 120 52 / 85 relapsed during or after prior systemic therapy, or are poorly responsive to established therapies that provide clinical benefit, or have developed intolerance to established therapies that provide clinical benefit; and have completed all prior therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or experimental therapy) for the treatment of cancer >1 week before the start of study therapy.

[139] Patients who are on ongoing immunosuppressive therapy in addition to corticosteroids may be excluded from treatment. At the time of initiation of study therapy, individuals may be using systemic corticosteroids (at doses <10 mg / day of prednisone or equivalent) or topical, inhaled, or intra-articular corticosteroids. During study therapy, individuals may use systemic, enteric, topical, inhaled, or intra-articular corticosteroids as required (e.g., for intercurrent medical conditions or antiemetic prophylaxis). PREMEDICATIONS

[140] To prevent tumor lysis syndrome (TLS), patients may receive allopurinol, 100 to 300 mg orally every 8 hours, starting >24 to 48 hours before the start of therapy with the study drug. Alternative drugs (e.g., febuxostat) may be substituted, administered according to the product label. In addition, individuals with hyperuricemia may receive rasburicase, 3 to 4.5 mg by IV infusion. Furthermore, high-risk individuals may receive rasburicase, 3 to 4.5 mg by IV infusion, administered 3 to 4 hours before the first dose of the study drug.

[141] If infusion reactions are observed, individuals may be premedicated prior to ADC-A infusions with an antipyretic and an antihistamine to reduce the incidence and severity of infusion reactions. The regimen may be an oral or IV antipyretic (acetaminophen [paracetamol], 650 to 1,000 Petition 870260064342, dated 06 / 30 / 2026, page 65 / 120 53 / 85 mg or equivalent) and an oral or IV antihistamine (cetirizine, 10 mg or equivalent), administered 30 to 60 minutes before each ADC-A infusion. A nonsteroidal anti-inflammatory drug (NSAID) (ibuprofen, 400 to 800 mg orally or equivalent) may be added or substituted for paracetamol. A corticosteroid (100 mg prednisolone or equivalent) may be considered as a premedication, as needed. EFFICACY EVALUATIONS Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

[142] Responses will be categorized as complete response without measurable residual disease (CRmrd-), complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), partial response with lymphocytosis (PR-L), stable disease (SD), or progressive disease (PD). In addition, a non-evaluable (NE) response category is provided for situations where there is inadequate information to categorize the response status.

[143] The best overall response will be determined. The best overall response is the best recorded response from the start of treatment to PD / recurrence. The screening measurement will be taken as a reference for response determinations. The nadir measurement will be considered a reference for PD; this measurement constitutes the lowest recorded measurement, including the screening measurement if this is the lowest measurement. Where imaging data are available, this data will replace physical examination data in determining tumor status. (1) Complete Response without Measurable Residual Disease (1) To meet the criteria for CRmrd-, all of the following conditions must be met: • All criteria for CR are met; • Flow cytometry of bone marrow aspirate shows cells Petition 870260064342, dated 06 / 30 / 2026, page 66 / 120 54 / 85 malignant <1 χ ΙΟ'4; (2) Complete Answer To meet CR criteria, all of the following conditions must be met: • No evidence of new disease; • ALC in peripheral blood of <4 χ 109 / l_; • Regression of all nodal index masses to normal size <15 mm in the left ventricle; • Normal spleen and liver size; • Regression to normal of all non-index nodal diseases and disappearance of all detectable non-nodal and non-index diseases; • Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular for age. • Peripheral blood meeting all of the following criteria: • ANC >1.5 χ 109 / L without exogenous growth factors <2 weeks before the relevant blood count assessment; • Platelet count >100 χ 109 / L without exogenous growth factors or platelet transfusions <2 weeks before the relevant blood count assessment; and • Hemoglobin >110 g / L (11.0 g / dL) without exogenous growth factors or red blood cell transfusions <2 weeks before the relevant blood count assessment. (3) Complete Response with Incomplete Count Recovery To satisfy the criteria for CRi, all criteria for CR are met, except for >1 of the following existing conditions: • ANC <1.5 x 109 / L or requires exogenous growth factors <2 weeks Petition 870260064342, dated 06 / 30 / 2026, page 67 / 120 55 / 85 before evaluating the relevant blood count to maintain an ANC >1.5 x 109 / L; • Platelet count <100 x 109 / L or requires exogenous growth factors or platelet transfusions <2 weeks before the relevant blood count assessment to maintain a platelet count >100 x 109 / L; • Hemoglobin <110 g / L (11.0 g / dL) or requires exogenous growth factors or red blood cell transfusions <2 weeks before the relevant blood count assessment to maintain a hemoglobin >110 g / L (11.0 g / dL); (4) Partial Response To meet the criteria for a PR, all of the following conditions must be met: • No evidence of new disease; • A change in disease status meeting >2 of the following criteria, with the exception that if only lymphadenopathy is present at screening, only lymphadenopathy must improve to the extent specified below: • Decrease in peripheral blood ALC of >50% from screening; • A decrease of >50% from the SPD screening of nodal index lesions; • In an individual with splenic enlargement at screening (>120 mm), a decrease of >50% from screening (minimum decrease of 20 mm) in splenic enlargement at their LVD or to <120 mm by imaging; • In an individual with liver enlargement at screening (>180 mm), a decrease of >50% from screening (minimum decrease of 20 mm) in liver enlargement at their LVD or to <180 mm by imaging; • A decrease of >50% from screening in CLL / SLL bone marrow infiltrate or in B lymphoid nodules; • Splenic, hepatic, or non-index disease with worsening that meets the criteria for definitive PD; Petition 870260064342, dated 06 / 30 / 2026, page 68 / 120 56 / 85 • Peripheral blood finding >1 of the following criteria: • ANC >1.5 x 109 / L or >50% increase from screening without exogenous growth factors (e.g., G-CSF) <2 weeks before relevant blood count assessment; • Platelet count >100 x 109 / L or >50% increase from screening without exogenous growth factors or platelet transfusions <2 weeks before relevant blood count assessment; • Hemoglobin >110 g / L (11.0 g / dL) or >50% increase from screening without exogenous growth factors (e.g., erythropoietin) or red blood cell transfusions <2 weeks before relevant blood count assessment; (5) Partial Response with Lymphocytosis To meet the criteria for a PR-L, the following conditions must be met: • No evidence of new disease; • All criteria for PR met, except for the lack of a decrease in peripheral blood ALC by >50% from screening; (6) Stable Disease To meet the criteria for SD, the following conditions must be met: • No evidence of new disease; • There is insufficient evidence of tumor shrinkage to qualify for PR nor sufficient evidence of tumor growth to qualify for definitive PD; (7) Progressive Disease The occurrence of any of the following events indicates definitive PD: • Evidence of any new disease: Petition 870260064342, dated 06 / 30 / 2026, page 69 / 120 57 / 85 • A new nodule measuring >15 mm in any diameter; • in an individual with a normal LVD of the spleen (i.e., an LVD of <120 mm per image) at nadir, a spleen LVD of >140 mm per image; • in an individual with a normal hepatic LVD (i.e., an LVD of <180 mm on imaging) at nadir, a liver LVD of >200 mm on imaging; • New non-index disease (e.g., effusions, ascites, or other organ abnormalities related to CLL / SLL); • Evidence of worsening of index lesions, spleen or liver, or non-index disease: • Increase in nadir by >50% of the nadir in the SPD of index lesions; • Increase in nadir by >50% in the LD of an individual nodule or extranodal mass that now has an LD of >15 mm and a LPD of >10 mm; • In an individual with splenic enlargement on screening (>120 mm), an increase of >50% in splenic enlargement (minimum increase of 20 mm) from the nadir; • In an individual with liver enlargement at screening (>180 mm), an increase of >50% from the screening nadir (minimum increase of 20 mm); • Unequivocal increase in the size of non-index disease (e.g., effusions, ascites, or other organ abnormalities related to CLL / SLL); • Transformation into a more aggressive histology (e.g., RTL), as established by lymph node biopsy (with the date of the lymph node biopsy being considered the date of CLL / SLL progression if the individual has no prior objective documentation of CLL / SLL progression); • A decrease in platelet or hemoglobin count that is attributable to CLL / SLL, is not attributable to an autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of clonal CLL / SLL cells; • The current platelet count is <100 χ 109 / L and there has been a decrease Petition 870260064342, dated 06 / 30 / 2026, page 70 / 120 58 / 85 of >50% from baseline; • Current hemoglobin is <110 g / L (11.0 g / dL) and there has been a decrease of >20 g / L (2 g / dL) from baseline; LYMPHOMA

[144] Responses will be categorized as complete response without measurable residual disease (CRmrd-), complete response (CR), very good partial responses (VGPR; LPL / WM only), partial response (PR), minor response (MR; LPL / WM only), stable disease (SD), or progressive disease (PD). In addition, a non-evaluable (NE) response category is provided for situations where there is inadequate information to categorize the response status.

[145] The best overall response will be determined. The best overall response is the best response during treatment, from the screening recorded from the start of treatment until PD / recurrence. The screening measurement will be taken as a reference for response determinations. The nadir measurement will be considered a reference for PD; this measurement constitutes the lowest recorded measurement, including the screening measurement if this is the lowest measurement. For FDG-avid tumors, metabolic criteria for PET-CT response will take precedence over anatomical criteria for contrast-enhanced CT response when assessing CR. (1) Complete Response without Measurable Residual Disease To meet the criteria for CRmrd-, all of the following conditions must be met: • All criteria for CR are met; • Flow cytometry of a bone marrow aspirate shows malignant cells <1x10-4; (2) Complete Answer To meet CR criteria, all of the following conditions must be met. Petition 870260064342, dated 06 / 30 / 2026, page 71 / 120 59 / 85 reached: • No evidence of new disease; • Regression of all nodal index lesions to <15 mm in the right lobe; • Regression to <15 mm of all non-index nodal diseases; • Disappearance of all detectable index and non-index extranodal diseases; • Normal spleen size of >130 mm in LVD by imaging studies; • If PET scan is performed, no evidence of residual disease - that is, a score of 1 (no uptake above the previous level), 2 (uptake < mediastinum) or 3 (uptake > mediastinum, but < liver) on the 5-point Deauville scale; • Negative for bone marrow involvement by PET for a PET-avid tumor or by morphological evaluation of a unilateral fragment biopsy; if the bone marrow biopsy is indeterminate by morphology, it must be negative by immunohistochemistry; • Absence of serum M protein by SIFE (in individuals with LPL / WM). (3) Very Good Partial Response (LPL / WM only) To meet VGPR criteria, all of the following conditions must be met: • All anatomical criteria for CR are met; • A decrease of >90% from baseline in serum M protein concentration is documented. (4) Partial Response To meet PR criteria, all of the following conditions must be met: • No evidence of new disease; • A decrease of >50% from screening in the SPD of index lesions Petition 870260064342, dated 06 / 30 / 2026, page 72 / 120 60 / 85 nodal and extranodal; • No increase from the nadir in the size of the non-index disease; • In an individual with splenic enlargement on screening, a decrease of >50% from screening (minimum decrease of 20 mm) in splenic enlargement in its longest vertical dimension (LVD) or to <130 mm per image; • If PET is performed: • Typically FDG-avid lymphoma: if no screening PET scan was performed or if the PET scan was positive before therapy, the treatment PET is positive at 1 previously involved site – i.e., a score of 4 (moderate uptake > liver) or a score of 5 (significant uptake > liver) on the 5-point Deauville scale, but with reduced uptake compared to screening. If a screening PET was performed and was negative, there is no new PET evidence of disease. Reduced uptake is defined as a decrease of >25% in %ASUVmax. • Variably FDG-avid lymphoma / unknown FDG avidity: if no pre-treatment PET scan was performed or if the pre-treatment PET scan was negative for lymphoma, CT criteria should be used in evaluating the tumor during treatment. If the PET scan is positive before therapy, the PET scan during treatment is positive in >1 previously involved site. • Persistence of bone marrow involvement in an individual who meets the radiographic criteria for CR; • A decrease of >50%, but <90% from baseline in serum protein M concentration (in individuals with LPL / WM). (5) Secondary Response (LPL / WM only) To meet MR criteria, all of the following conditions must be met: Petition 870260064342, dated 06 / 30 / 2026, page 73 / 120 61 / 85 • Anatomical disease criteria for PR or SD are met; • A decrease of >25%, but <50% from baseline in serum protein M concentration is documented. (6) Stable Disease To meet SD criteria, all of the following conditions must be met: • No evidence of new disease; • Neither sufficient tumor shrinkage from screening to qualify for PR, nor sufficient evidence of tumor growth to qualify for PD; • If PET scans are performed, the results show a score of 4 (moderate uptake > liver) or a score of 5 (significant uptake > liver) on the 5-point Deauville scale with no significant change in uptake compared to screening; • A decrease of <25% and an increase of <25% from baseline in serum protein M concentration (in individuals with LPL / WM); (7) Progressive Disease The occurrence of any of the following events indicates PD: • Evidence of any new disease that was not present during screening: • A new nodule measuring >15 mm in any diameter; • Reappearance of an extranodal lesion that had resolved (i.e., a PPD of 0 mm2 had previously been assigned); • A new extranodal lesion >10 mm; • New non-index disease (e.g., effusions, ascites, or other organ abnormalities) of any size unequivocally attributable to lymphoma (usually requires PET, biopsy, cytology, or other non-radiological confirmation to confirm the disease is attributable to lymphoma). Petition 870260064342, dated 06 / 30 / 2026, page 74 / 120 62 / 85 • New FDG-avid foci consistent with lymphoma, rather than another etiology (e.g., infection, inflammation). If there is uncertainty regarding the etiology of new lesions, biopsy or interval screening may be considered. • New or recurrent bone marrow involvement with lymphoma by PET scan or bone marrow biopsy if a previous PET scan or bone marrow biopsy performed as part of the study was negative for lymphoma. • Evidence of worsening of nodal or extranodal index lesions: • Increase in nadir by >50% in the SPD of index lesions; • Evidence of worsening of individual index lymph nodes or nodal masses with an increase from the nadir of >50% in PPD for any individual node if the node now has a LD of >15 mm, an increase of >50% in the nadir PPD, and an increase in LD or SDi from the nadir of: • >5 mm for lesions measuring <20 mm (in LD or SDi) or, • >10 mm for lesions measuring >20 mm (in LD or SDi); • Unequivocal increase in the size of the non-index disease; • An increase in splenic magnification of >50% (minimum increase of 20 mm) from nadir in a patient with a splenic LVD of >130 mm on imaging at nadir, or a splenic LVD of >150 mm on imaging in a patient with a splenic LVD of <130 mm on imaging at nadir; • Transformation into a more aggressive NHL histology, as established by lymph node biopsy; • If PET is performed, there is a score of 4 (moderate uptake >liver) or a score of 5 (significant uptake >liver) on the 5-point Deauville scale with an increase in uptake compared to the nadir in conjunction with an anatomical increase in lesion size consistent with PD. Increased uptake is defined as an increase >50% in %ΔSUVmax; Petition 870260064342, dated 06 / 30 / 2026, page 75 / 120 63 / 85 • An increase from the nadir of >25% in serum protein M concentration (in individuals with LPL / WM). Acute Lymphoblastic Leukemia

[146] Responses will be categorized as complete response without measurable residual disease (CRmrd-), complete response (CR), complete response with incomplete blood count recovery (CRi) (including unconfirmed complete response [CRu] for individuals with mediastinal disease), partial response (PR), stable disease (SD), treatment failure (TF), or disease recurrence or progression (DRP). In addition, a non-evaluable (NE) response category is provided for situations where there is inadequate information to categorize the response status.

[147] The best overall response will be determined. The best overall response is the best response to treatment from baseline recorded from the start of treatment to the DRP. The baseline measurement will be considered a reference for response determinations. The nadir measurement will be taken as a reference for DRP; the best measurement in the study constitutes the measurement with the least tumor involvement, including the baseline measurement if this is the measurement that meets this criterion. (1) Complete Response without Measurable Residual Disease To meet the criteria for CRmrd-, all of the following conditions must be met: • All criteria for CR are met; • Flow cytometry of a bone marrow aspirate shows malignant cells <1x10-4. (2) Complete Answer To meet CR criteria, all of the following conditions must be met: Petition 870260064342, dated 06 / 30 / 2026, page 76 / 120 64 / 85 • Leukemic disease status meeting all of the following requirements: <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); o No blasts in peripheral blood; No extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass and no central nervous system involvement [i.e., reaching CNS-1 status {no blasts in cerebrospinal fluid]); • Peripheral blood meeting all of the following requirements: ANC > 1.0 x 109 / L; Platelet count >100 x 109 / L; • Any mediastinal enlargement shows complete resolution as documented radiographically. (3) Complete Response with Incomplete Blood Count Recovery and / or Complete Response Not Confirmed To meet the criteria for CRi / CRu, all of the following conditions must be met: • Leukemic disease status meeting all of the following requirements: <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); o No blasts in peripheral blood; No extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass, and no central nervous system involvement [i.e., reaching CNS-1 status {no blasts in cerebrospinal fluid}). Petition 870260064342, dated 06 / 30 / 2026, page 77 / 120 65 / 85 • Peripheral blood that meets any of the following requirements: ANC <1.0 x 109 / L; • Platelet count <100 x 109 / L; • Any mediastinal enlargement regressed by >75% in the sum of the products of perpendicular diameters (SPD), as documented radiographically. (4) Partial Response To meet PR criteria, all of the following conditions must be met: • Leukemic disease status meeting one of the following requirements: A decrease of >50% in bone marrow blasts to 5% to 25% (inclusive) (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); o No blasts in peripheral blood; No new or worsening extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass, or central nervous system involvement [e.g., CNS-1 status {no blasts in cerebrospinal fluid} has not transitioned to CNS-2 status {WBC < 5 x 109 / L with blasts in cerebrospinal fluid} or to CNS-3 status {WBC >5 x 109 / L with blasts in cerebrospinal fluid} or to the development of facial nerve palsy, brain / eye involvement, or hypothalamic syndrome]); • Peripheral blood meeting all of the following requirements: ANC >1.0 x 109 / L; Platelet count >100 x 109 / L; • Any mediastinal enlargement regressed by >50% in the SPD, as documented radiographically; Petition 870260064342, dated 06 / 30 / 2026, page 78 / 120 66 / 85 (5) Stable Disease / Treatment Failure To meet SD criteria, all of the following conditions must be met: • Neither sufficient improvement in ALL from baseline to qualify for PR nor sufficient evidence of ALL worsening to qualify for DRP; • No new or worsening extramedullary disease (including lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass, or central nervous system involvement [e.g., CNS-1 status {no blasts in cerebrospinal fluid} has not transitioned to CNS-2 status {WBC < 5 x 109 / L with blasts in cerebrospinal fluid} or to CNS-3 status {WBC >5 x 109 / L with blasts in cerebrospinal fluid} or to the development of facial nerve palsy, brain / eye involvement, or hypothalamic syndrome); • No development of new mediastinal enlargement and no increase in SPD of existing mediastinal enlargement >25%; An individual without DRP who does not qualify for a CRmrd-, CR, CRi / CRu, or PR for 18 weeks (for Schedules 1 and 2) or 16 weeks (for Schedule 3) from the start of study therapy will be considered to have TF. (6) Recurrence or Progression of the Disease The occurrence of any of the following events indicates DRP: • Reappearance of blasts in the bone marrow (for >5%) in an individual who has had a CR; • Reappearance of blasts in the peripheral blood of an individual who has experienced a CR; • An increase of >25% in bone marrow blasts to >20% (based on a bone marrow aspirate / biopsy sample with >200 cells) Petition 870260064342, dated 06 / 30 / 2026, page 79 / 120 67 / 85 nucleated and the presence of bone marrow spicules); • An increase of >25% in blasts in peripheral blood to >1 x 109 / L. • Development of new or worsened existing extramedullary disease (involving lymphadenopathy, splenomegaly, skin / gum infiltration, testicular mass, or CNS involvement [e.g., CNS-1 state {no blasts in cerebrospinal fluid} transitioned to CNS-2 state {white blood cells < 5 x 109 / L with blasts in cerebrospinal fluid} or to CNS-3 state {WBC >5 x 109 / L with blasts in cerebrospinal fluid} or to the development of facial nerve paralysis, brain / eye involvement, or hypothalamic syndrome); • Development of new mediastinal enlargement or enlargement in SPD of existing mediastinal enlargement >25%. Acute myeloid leukemia

[148] Responses will be categorized as complete response without measurable residual disease (CRmrd-), complete response (CR), complete response with incomplete blood count recovery (CRi), morphological leukemia-free status (MLFS), partial response (PR), stable disease (SD), treatment failure (TF), or disease recurrence or progression (DRP). In addition, a non-evaluable (NE) response category is provided for situations where there is inadequate information to categorize the response status.

[149] The best overall response will be determined. The best overall response is the best treatment response from baseline recorded from the start of treatment until PRD or TF. Baseline status will be taken as a reference for response determinations. The best study measurement will be taken as a reference for PRD; the best study measurement constitutes the measurement with the least tumor involvement, including the baseline measurement if this is the measurement that meets this criterion. Petition 870260064342, dated 06 / 30 / 2026, page 80 / 120 68 / 85 (1) Complete Response without Measurable Residual Disease To meet the criteria for CRmrd-, all of the following conditions must be met: • All criteria for CR are met; • Flow cytometry of a bone marrow aspirate shows malignant cells <1x10-4; (2) Complete Answer To meet CR criteria, all of the following conditions must be met: • Leukemic disease status meeting all of the following requirements: <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); o No blasts in peripheral blood; Without blasts with Auer rods; No extramedullary disease; • No peripheral blood meeting the following requirements: ANC >1.0 x 109 / L; Platelet count >100 x 109 / L. (3) Complete Response with Incomplete Blood Count Recovery To meet the criteria for CRi, all of the following conditions must be met: • Leukemic disease status meeting all of the following requirements: <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); o No blasts in peripheral blood; Petition 870260064342, dated 06 / 30 / 2026, page 81 / 120 69 / 85 No explosions with Auer blasts; No extramedullary disease. • Peripheral blood meeting only 1 of the following criteria: ANC >1.0 x 109 / L; • Platelet count >100 x 109 / L. (4) Morphological Leukemia-Free State To meet the MLFS criteria, all of the following conditions must be met: • Leukemic disease status meeting all of the following requirements: <5% bone marrow blasts (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells, >10% cellularity, and the presence of bone marrow spicules); o No blasts in peripheral blood; Without blasts with Auer rods; No extramedullary disease. • Peripheral blood meeting both of the following criteria: ANC <1.0 x 109 / L; Platelet count <100 x 109 / L. (5) Partial Response To meet PR criteria, all of the following conditions must be met: • Leukemic disease status meeting one of the following requirements: A decrease of >50% in bone marrow blasts to 5% to 25% (inclusive) (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules); <5% of bone marrow blasts, but with Auer rods present (based on a bone marrow aspirate / biopsy sample with >200 Petition 870260064342, dated 06 / 30 / 2026, page 82 / 120 70 / 85 nucleated cells and the presence of bone marrow spicules); o No blasts in peripheral blood; No new or worsened extramedullary disease. • Peripheral blood meeting both of the following criteria: ANC > 1.0 x 109 / L; Platelet count >100 x 109 / L. (6) Stable Disease / Treatment Failure To meet SD criteria, all of the following conditions must be met: • Neither sufficient improvement in AML from baseline to qualify for CRmrd-, CR, CRi, MLFS, or PR, nor sufficient evidence of worsening AML to qualify for DRP; • No new or worsening extramedullary disease. An individual without DRP who does not qualify for a CRmrd-, CR, CRi, MLFS, or PR for 18 weeks (for Schedules 1 and 2) or 16 weeks (for Schedule 3) from the start of study therapy will be considered to have TF. (7) Relapse or Progression of the Disease The occurrence of any of the following events indicates DRP: • Reappearance of bone marrow blasts to >5% in an individual who has experienced a CRmrd-, CR, CRi, or MLFS; • Reappearance of blasts in the peripheral blood of an individual who has experienced CRMRD-, CR, CRi, MLFS, or PR; • An absolute increase of 20% in bone marrow blasts to >25% (based on a bone marrow aspirate / biopsy sample with >200 nucleated cells and the presence of bone marrow spicules) in an individual who had a PR; Petition 870260064342, dated 06 / 30 / 2026, page 83 / 120 71 / 85 • An absolute increase of 20% in peripheral blasts to >25% in an individual who had a PR; • Development of a new extramedullary disease or worsening of an existing extramedullary disease. Recurrence or worsening of MRD, assessed by flow cytometry, will not be considered in the definition of PRD, but will be recorded. LABORATORY AND OTHER ASSESSMENTS

[150] The samples to be obtained and the parameters to be analyzed are indicated in Table 6. Table 6. Laboratory and Other Parameters to be Evaluated Test or Procedure Parameters Safety (analyzed in a local clinical laboratory) Urinalysis • Strip: specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, leukocyte esterase. • Microscopy: White blood cells, red blood cells, epithelial cells, bacteria, casts, crystals. Serum Virology • Serum antibody for HIV. • Serum HBsAg antibody, HBc antibody (or serum HBV DNA by PCR). • Serum HCV antibody (or serum HCV RNA by PCR). Serum Pregnancy Test • Serum β-HCG. Serum Chemistry • Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphorus, magnesium, total protein, albumin, ALT, AST, ALP, CK, LDH, total bilirubin, acid Petition 870260064342, dated 06 / 30 / 2026, p. 84 / 120 72 / 85 Test or Procedure Parameters uric acid, amylase, lipase. Hematology • Hematocrit, hemoglobin, red blood cell count. • Absolute counts of leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils. • Platelet count. Coagulation • PT. • aPTT. Pharmacokinetics (analyzed in a contracted laboratory) Pharmacokinetics of ADC-A and MMAE • Plasma concentrations of ADC-A (as assessed by a validated bioanalytical method), including: o Total ADC-A, defined as the complete antibody-ligand conjugate-MMAE (considering the mean DAR to derive the total ADC-A value). o Total antibody, defined as total ADC-A plus any antibody that is not conjugated with MMAE. • Plasma concentrations of MMAE (as assessed by a validated bioanalytical method). • Plasma retention for analysis of potential metabolites.Immunogenicity (analyzed in a contracted laboratory) Serum for ADC-A immunogenicity • ADA titers and neutralizing capacity (as assessed by a validated immunoassay). • Serum retention for parameter analysis. Petition 870260064342, dated 06 / 30 / 2026, page 85 / 120 73 / 85 Test or Procedure Alternative safety parameters. Pharmacodynamics (analyzed in contracted laboratories) Plasma pharmacodynamics • Plasma concentrations of Wnt5 (as measured using immunoassay methods). • Plasma concentrations of ROR1 (as measured using immunoassay methods). • Chemokines and cytokines, potentially including (but not limited to): CCL2, CCL3, CCL4, CCL7, CCL17, CCL19, CCL21, CCL22, CXCL12, CXCL13, CD40 ligand and TNFα (as measured using immunoassay methods). • Plasma retention for potential additional cytokine / chemokine analyses, ADC-A concentration analysis, or alternative safety parameter analysis. Blood for ROR1 / other markers (CLL / SLL, MCL, NHL T cells, ALL and AML) • Numbers of circulating tumor cells expressing ROR1 and other proliferation / apoptosis markers (e.g., Ki67, caspase) (as measured using flow cytometry).Blood for T, B, and NK cell profiles • Numbers of circulating T cells, B cells, NK cells, and monocyte subsets (as measured using flow cytometry). Disease-related biomarkers (analyzed in contracted laboratories). Petition 870260064342, dated 06 / 30 / 2026, page 86 / 120 74 / 85 Test or Procedure Parameters Tumor (from peripheral blood, bone marrow, or tumor biopsy) for ROR1 / other profiles • Baseline ROR1 tumor protein expression (as assessed by immunohistochemistry). • Baseline tumor mutation profile, gene expression, and / or protein gene expression (as assessed by NanoString technology). • Cell of origin (DLBCL only) (as assessed by NanoString Lymph2Cx). Disease-Related Efficacy (analyzed at a contract laboratory or local clinical laboratory (for M protein)) Bone marrow biopsy and aspirate (in individuals with CLL / SLL or NHL) • Bone marrow biopsy for hematologic cancer disease status analysis (as assessed by hematoxylin and eosin, immunohistochemistry, and / or FISH [as needed for ambiguous disease analysis]). • Bone marrow aspirate for MRD status (as assessed by flow cytometry).Peripheral blood smears and bone marrow biopsy and aspirate (in individuals with ALL or AML) • Peripheral blood smears for analysis of ALL / AML disease status (percentage of blast, presence of Auer rods [AML] (as assessed by Wright staining)). • Bone marrow aspirate for analysis of ALL / AML disease status (percentage of blast, presence of Auer rods [AML]) (as assessed by Wright staining) and MRD status (as assessed by flow cytometry). • Bone marrow biopsy for analysis of the status of... Petition 870260064342, dated 06 / 30 / 2026, page 87 / 120 75 / 85 Test or Procedure Parameters Hematologic cancer disease (as assessed by hematoxylin and eosin, immunohistochemistry, and / or FISH [as needed for ambiguous disease analysis]). Serum M protein (in individuals with LPL / WM) • Serum immunoglobulin concentrations (as assessed by SPEP and SIFE) Disease-Related Efficacy (analyzed at a contracted radiographic imaging unit) Radiology Examination • Imaging of the neck, chest, abdomen, and pelvis (by CT, PET / CT, or MRI, as appropriate for disease type and tumor status). Other (analyzed on-site - except ECG, which is analyzed at a contracted cardiology unit) Body weight / height • Weight in kilograms, height in centimeters. Body temperature • Temperature in degrees Celsius. Blood pressure • Diastolic and systolic blood pressure in mm Hg. Oxygen saturation • % saturation. 12-lead ECG • Heart rate, heart rate intervals, waveform abnormalities, ectopic beats. Abbreviations: ADA = anti-drug antibodies, ALL = acute lymphoblastic leukemia, ALP = alkaline phosphatase, ALT = alanine aminotransferase, AML = acute myeloid leukemia, aPTT = activated partial thromboplastin time, AST = Petition 870260064342, dated 06 / 30 / 2026, page 88 / 120 76 / 85 aspartate aminotransferase, BUN = blood urea nitrogen, CCL = chemokine ligand (CC motif), CD = cluster of differentiation, CK = creatine kinase, CLL = chronic lymphocytic leukemia, CT = computed tomography, CXCL = chemokine ligand (CXC motif), DAR = drug-antibody ratio, DLBCL = diffuse large B-cell lymphoma, DNA = deoxyribonucleic acid, ECG = electrocardiogram, FDG = fluorodeoxyglucose, FISH = fluorescent in situ hybridization, HBc antibody = central anti-hepatitis B antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, IFNγ = interferon-γ, IL = interleukin, LDH = lactate dehydrogenase, LPL / WM = lymphoma lymphoplasmacytoid / Waldenstrom's macroglobulinemia, M protein = monoclonal immunoglobulin M protein, MMAE = monomethyl auristatin E, MRD = measurable residual disease, MRI = magnetic resonance imaging.NGS = next-generation sequencing, NK = natural killer (cells), PET = positron emission tomography, PCR = polymerase chain reaction, PT = prothrombin time, RNA = ribonucleic acid, ROR1 = orphan receptor tyrosine kinase type 1, SIFE = serum immunofixation electrophoresis, SPEP = serum protein electrophoresis, TNF = tumor necrosis factor, β-HCG = human chorionic gonadotropin β.

[151] The classification of adverse event severity, as applied in the present invention, is described in Table 7 below. Table 7. Classification of Severity of Adverse Event Degree Adjective Description Degree 1 Mild The sign or symptom is present but is easily tolerated, is not expected to have a clinically significant effect on the individual's overall health and well-being, and does not interfere with the Petition 870260064342, dated 06 / 30 / 2026, page 89 / 120 77 / 85 Grade 1 Adjective Description Normal function of the individual and is not likely to require medical attention. Grade 2 Moderate The sign or symptom interferes with normal activity or affects the clinical condition and may require medical intervention. Grade 3 Severe The sign or symptom is disabling or significantly affects the clinical condition and likely requires medical intervention and / or close monitoring. Grade 4 Life-threatening The sign or symptom results in a potential threat to life. Grade 5 Fatal The sign or symptom results in death. RESULTS I. SECURITY

[152] Data were obtained from 25 individuals with hematologic malignancies, including 12 individuals with MCL, 7 individuals with CLL / SLL, 2 individuals with DLBCL, 2 individuals with FL, 1 individual with MZL, and 1 individual with RTL. Individuals were heavily pretreated with a median (range) of 4 (1 to 23) prior systemic chemotherapy regimens, including hematopoietic stem cell transplantation (HSCT) in 4 individuals and chimeric antigen receptor (CAR) T-cell or natural killer (NK) cell therapy in 3 individuals.

[153] 96 doses of ADC-A were administered, including 1 at the 0.5 mg / kg dose level, 9 at the 1.0 mg / kg dose level, 18 at the 1.5 mg / kg dose level, 46 at the 2.25 mg / kg dose level, and 22 at the 2.5 mg / kg dose level. The number of therapy cycles received ranged from 1 to 10. All individuals received Petition 870260064342, dated 06 / 30 / 2026, pages 90 / 120 78 / 85 ADC-A in the Q1 / 3W administration schedule (Table 4).

[154] Treatment with ADC-A was generally well tolerated, with neutropenia being the primary acute toxicity. No DLTs were observed with doses of 0.5, 1.0, and 1.5 mg / kg. A Grade 4 neutropenia DLT in C1 was observed in 1 of 7 subjects receiving ADC-A 2.25 mg / kg. In addition, 1 subject receiving ADC-A 2.25 mg / kg experienced Grade 3 neutropenia in C1, and 1 subject receiving ADC-A 2.25 mg / kg experienced Grade 4 neutropenia in C2. In each of these 3 cases, neutropenia was observed approximately on Day 15 of the cycle. Neutropenia responded to granulocyte colony-stimulating factor (G-CSF) administered reactively or as secondary prophylaxis. Neutropenic fever or infection did not occur.An individual starting with ADC-A 2.5 mg / kg experienced Grade 4 thrombocytopenia in C1; however, this individual had a history of thrombocytopenia, including Grade 2 thrombocytopenia at baseline, their post-baseline platelet abnormalities were not clearly related to the drug, and they continued with C2 and C3 therapy with ADC-A 2.5 mg / kg.

[155] One individual experienced Grade 2 neuropathy following administration of 5 cycles of ADC-A 2.25 mg / kg; treatment was delayed for 1 cycle and therapy was resumed at a dose of 1.5 mg / kg. Other adverse events, laboratory abnormalities, and ECG findings were of low grade, did not appear to be dose- or exposure-dependent, and likely resulted from the underlying cancer, comorbid conditions, intercurrent illnesses, or concomitant medications. No infusion reactions or tumor lysis syndrome were observed. II. Pharmacokinetics

[156] Plasma concentrations of total ADC-A and MMAE over time for 16 patients dosed with ADC-A are shown in FIG. 1. The mean Petition 870260064342, dated 06 / 30 / 2026, pp. 91 / 120 Tmax of 79 / 85 occurred shortly after the end of the infusion for ADC (0.5 to 2 hours from the start of the 30-minute IV infusion) and 48 to 89 hours after the dose for MMAE. The corresponding pharmacokinetic parameters (PK) are shown in Table 8. Table 8. Pharmacokinetic Parameters of ADC-A Dos and Parameter T 1 max. Cmax Cmax / Dose AUCuiti m AUCLast / Dose Vz CL ti / 2 Ratio ADC / Antibody [0] Units hour Rg / m L h*Rg / mL mL / kg mL / min / kg days 0.5 mg / kg (n = 1) Antibody 2 12.4 25 1280 2560 49.4 0.00589 4.0 0.43 ADC 2 9.6 19 547 1094 82.4 0.01480 2.7 MMAE 48 0.001 15 0.0023 0.271 0.5420 1.0 mg / kg (n = 3) Antibody 2.2 20.1 20 1863 1863 49.2 0.00974 3.2 0.53 ADC 2 20.6 21 995 995 69.0 0.01700 2.1 MMAE 48 0.002 66 0.0027 0.467 0.4673 1.5 mg / kg (n = 3) Antibody 3.3 29.5 20 3890 2593 66.0 0.00525 6.2 0.61 ADC 1.7 31.3 21 2383 1589 63.4 0.01023 3.0 MMAE 88.7 0.001 66 0.0011 0.390 0.2600 Petition 870260064342, dated 06 / 30 / 2026, page 92 / 120 80 / 85 Dos and Parameter T 1 max. Cmax Cmax / Dose AUCuiti m AUCuiti m / Dose Vz CL ti / 2 Ratio ADC / Anticorpo [0] Units hour Rg / m L h*pg / mL mL / kg mL / min / kg day as 2.25 mg / kg (n = 9) Antibody 0.8 42.5 19 4020 1787 70.8 0.00935 4.4 0.66 ADC 0.5 49.3 22 2660 1182 70.9 0.01621 2.4 MMAE 75.1 0.004 43 0.0020 0.698 0.3102 2.5 mg / kg (n = 4) Antibody 2.1 48.02 5 19 4490.5 1796.2 68.0 0.00747 4.6 0.64 ADC 1.3 43.25 17 2967.5 1187 67.0 0.01297 2.6 MMAE 78.5 0.006 70 0.0027 0.994 75 0.3979 a. AUCmax for total ADC divided by AUCmax for total antibody. Abbreviations: ADC = antibody-drug conjugate, AUCultimate = area under the concentration-time curve to the last measurable concentration, CL = clearance, Cmax = maximum concentration, MMAE = monomethyl auristatin E, SD = standard deviation, t1 / 2 = half-life, Tmax = time to maximum concentration, Vz = volume of distribution

[157] Increases in Cmax and AUC were generally dose-proportional for ADC-A and somewhat less than dose-proportional for MMAE. Mean t1 / 2 values ​​for ADC-A ranged from 2.1 to 3.0 days, independent of the dose administered. Petition 870260064342, dated 06 / 30 / 2026, pp. 93 / 120 81 / 85

[158] Pharmacodynamic data from individuals with CLL showed concentration- and time-dependent occupancy of ROR1 receptors in circulating CLL cells (FIG. 2). Cells were isolated by Ficoll, stained with LIVE / Dead reagent, and then stained with CD19, CD5, UC961-PE, and 4A5 AlexaFluor647. At the respective ADC-A doses of 1.0 and 2.25 mg / kg, only 22.7% and 12.8% of ROR1 receptors were unoccupied at the end of the 30-minute IV infusion. The unoccupied receptors showed a time-dependent return to baseline that corresponded to simultaneous decreases in plasma ADC-A concentrations. At the 2.25 mg / kg dose level, target coverage appeared to decrease on Day 8 and was lost on Day 15, consistent with the decline in plasma ADC exposure.

[159] The correlation of unoccupied ROR1 receptors with plasma ADC-A concentrations, as shown in FIG. 3, allows the establishment of target plasma concentration values. Maintaining 50% receptor occupancy (50% of receptors unoccupied) requires a plasma ADC-A concentration of 1.7 pg / mL. Maintaining 75% receptor occupancy (25% of receptors unoccupied) requires a plasma ADC-A concentration of 5.8 pg / mL. Maintaining 90% receptor occupancy (10% of receptors unoccupied) requires a plasma ADC-A concentration of 35 pg / mL.

[160] Pharmacokinetic simulations were performed to further explore potential ADC-A dosing regimens. The simulations indicate that weekly administration of ADC-A may be more effective than administration once every three weeks (FIG. 4 and Table 9). A weekly dosing regimen may provide more continuous ADC-A exposure and target ROR1 occupancy, allowing myeloid recovery before the next treatment cycle and may be useful for an induction regimen (e.g., Q2 / 3W or Petition 870260064342, dated 06 / 30 / 2026, pp. 94 / 120 82 / 85 Q3 / 4W) followed by a maintenance regime with less frequent administration (e.g., Q1 / 3W). Table 9. Maintenance of ROR1 Occupancy over 12 weeks ADC-A dose per infusion, mg / kg Schedule Cycles, n Total Duration, Weeks Total Doses per 12-week period, n Time Proportion (%) in 12 Weeks to Achieve Designated ROR1 Occupancy >50% >75% >90% 1.25 D1, D8, D15, Q4W 3 12 9 78.1 41.5 0.0 1.50 D1, D8 Q3W 4 12 8 73.4 41.7 0.0 2.50 D1 Q3W 4 12 4 46.4 27.8 0.6 III. ANTITUMORAL RESPONSE

[161] Antitumor activity was observed in individuals heavily pretreated with MCL (including three partial responses) and DLBCL (including one partial response) (FIG. 5) upon treatment with ADC-A using the Q1 / 3W dosing regimen.

[162] An individual with MCL presented with extensive pre-existing disease, with lesions on the palate, neck, chest, abdomen, and pelvis. The individual had received prior heavy R-hyper-CVAD therapy with R / methotrexate / cytarabine, rituximab, ibrutinib, daratumumab, lenalidomide-rituximab, and radiotherapy. The individual showed evidence of an objective tumor response to treatment with 2.25 mg / kg of ADC-A over three cycles. All measured nodal clusters showed a reduction in tumor dimensions, with a 53% decrease in SPD (sum of the products of the Petition 870260064342, dated 06 / 30 / 2026, pp. 95 / 120 83 / 85 perpendicular diameters). In addition, a lesion on the palate also decreased in size and tissue infiltration. The magnitude of the response appears to qualify as a partial response (PR). The individual did not exhibit signs of any hematological or non-hematological toxicity related to the drug.

[163] Another individual with MCL exhibited a mass on the palate and extranodal disease, and had received prior heavy therapy with rituximab, rituximab / bortezomib, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), BR (bendamustine and rituximab, R-hyper-CVAD with intrathecal prophylaxis), ibrutinib, and mosunetuzumab. The individual showed evidence of an objective tumor response to treatment with 2.5 mg / kg of ADC-A over three cycles. The individual reported that their activity had increased and fatigue had largely disappeared; additionally, the palate lesion decreased in size by 85%. The magnitude of the response appears to qualify as a partial response (PR).

[164] Another individual with MCL presented with orbital lesions and extranodal disease, and had received prior heavy therapy with R-CHOP, rituximab, ibrutinib-rituximab, and rituximab-BEAM (carmustine, cytarabine, etoposide, and melphalan). The individual showed evidence of an objective tumor response to treatment with 2.5 mg / kg of ADC-A over six cycles, with a 51% decrease in SPD for tumor lesions. The magnitude of the response appears to qualify as a partial response (PR).

[165] An individual with DLBCL presented with extranodal disease and had received prior heavy therapy with R-CHOP, R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, and cisplatin), R-GEMOX (rituximab, gemcitabine, and oxaliplatin), BEAM plus autologous transplantation, pinatuzumab-rituximab, bendamustine-rituximab, and CAR-T cells with conditioning. Petition 870260064342, dated 06 / 30 / 2026, page 96 / 120 84 / 85 fludarabine. The individual showed evidence of an objective tumor response to ADC-A treatment over six cycles (2.25 mg / kg in Cycle 1, a reduced dose in Cycle 2, 2.25 mg / kg in Cycles 3-5, and 2.5 mg / kg in Cycles 6 and 7). Both measured nodal groups showed reductions in tumor dimensions, with a 68% decrease in SPD. The magnitude of the response appears to qualify as a partial response (PR).

[166] Although preferred embodiments of the present invention have been shown and described in the present invention, it will be obvious to those skilled in the art that such embodiments are provided only as examples. Numerous variations, alterations and substitutions will now occur to those skilled in the art without departing from the spirit of the invention. It should be understood that various alternatives to the embodiments of the invention described in the present invention may be employed in the practice of the invention.

[167] The amino acid sequences described in the present invention are listed in Table 10 below. Table 10. List of Sequences SEQ Description SEQUENCE 1 Heavy chain Ab1 QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPG QGLEWMGSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTM TNMD PVDTATYYCARGWYYF DYWG H GTLVTVSSASTKG PSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC Petition 870260064342, dated 06 / 30 / 2026, page 97 / 120 85 / 85 SEQ Descrição SEQUÊNCIA SVM HEALHN HYTQKSLSLSPGK 2 Cadeia line Ab1 DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQA PRLLIYSGSTLQSGIPPRFSGSGYGTDFTLTIN NIESEDAAYYFC QQH DESPYTFGEGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 3 Ab1 VH QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPG QGLEWMGSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTM TNMDPVDTATYYCARGWYYFDYWGHGTLVTVSS 4 Ab1 VL DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQA PRLLIYSGSTLQSGIPPRFSGSGYGTDFTLTIN NI ESEDAAYYFC QQHDESPYTFGEGTKVEIK 5 Ab1HCDR1 GYAFTAYN 6 Ab1HCDR2 FDPYDGGS 7 Ab1HCDR3 GWYYFDY 8 Ab1LCDR1 KSISKY 9 Ab1LCDR2 SGS 10 Ab1LCDR3 QQHDESPY *SEQ: SEQ ID NO:

Claims

1. Use of an immunoconjugate of Formula (I): cr nh2 (I), comprising an antibody conjugated to a ligand / payload, wherein: Ab is an antibody that binds to ROR1, comprising: (i) a variable heavy chain region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6 and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 7, and (ii) a variable light chain region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 9 and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 10; The ligand / payload has the structure: nh2, characterized by the fact that it is for the manufacture of a pharmaceutical composition to treat hematological cancer in a patient, in which the number of ligand / payload fractions per antibody is from 1 to 7, Petition 870260064342, dated 06 / 30 / 2026, page 1.99 / 120 2 / 7 wherein the pharmaceutical composition is formulated to provide a dose of 0.25 to 4.00 mg / kg; and (i) wherein the pharmaceutical composition is formulated to be administered in three-week cycles and administered on day 1 of each cycle at said dose; (ii) wherein the pharmaceutical composition is formulated to be administered in three-week cycles and administered on days 1 and 8 of each cycle at said dose; or (iii) wherein the pharmaceutical composition is formulated to be administered in four-week cycles and administered on days 1, 8 and 15 of each cycle at said dose.

2. Use according to claim 1, characterized in that the number of ligand / payload fractions per antibody is 3 to 5.

3. Use according to claim 1 or 2, characterized in that the dose is 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75 or 3.00 mg / kg.

4. Use according to claim 1, characterized in that the number of cycles is 3 or more.

5. Use in accordance with any one of claims 1 to 3, characterized in that the pharmaceutical composition is formulated to be administered: a) weekly for the first three weeks and then every three weeks; b) weekly for the first four weeks and then every three weeks; c) weekly for the first six weeks and then every three weeks; d) weekly for the first eight weeks and then every three weeks; e) every three weeks for the first three weeks and then weekly; Petition 870260064342, dated 06 / 30 / 2026, p. 100 / 120 3 / 7 f) every three weeks for the first six weeks and then weekly; or g) every three weeks for the first nine weeks and then weekly.

6. Use in accordance with any one of claims 1 to 5, characterized in that the pharmaceutical composition is formulated to be administered intravenously.

7. Use in accordance with any of claims 1 to 6, characterized in that the cancer is selected from the group consisting of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), Richter transforming lymphoma (RTL), Burkitt lymphoma (BL), lymphoplasmacytoid lymphoma (LPL), Waldenstrom macroglobulinemia (WM), T-cell non-Hodgkin lymphoma, acute lymphocytic leukemia (ALL), and acute myeloid leukemia (AML).

8. Use in accordance with any of claims 1 to 7, characterized in that the patient has been previously treated for cancer.

9. Use in accordance with any of claims 1 to 8, characterized in that the cancer is recurrent or refractory to treatment.

10. Use in accordance with any of claims 1 to 9, characterized in that treatment with the pharmaceutical composition results in one or more of the following: a) induction of tumor regression; b) delay of tumor progression; c) inhibition of cancer metastasis; d) prevention of cancer recurrence or residual disease; e) decreased size of nodal or extranodal tumor masses; f) a decrease in the number of malignant cells in the bone marrow and peripheral blood; g) a decrease in hepatomegaly or malignant splenomegaly; h) improvement in cancer-related anemia, neutropenia or thrombocytopenia; i) alleviation of cutaneous manifestations; j) decreased probability of hyperviscosity syndrome in patients with LPL / WM; k) alleviation of disabling constitutional symptoms; el) prolonged survival.

11. Use in accordance with any of claims 1 to 10, characterized in that treatment with the pharmaceutical composition results in the complete eradication of the tumor.

12. Immunoconjugate, characterized by the fact that it is for use in the treatment of hematological cancer in a patient, wherein the immunoconjugate is represented by Formula (I): (I), comprising an antibody conjugated to a ligand / payload, wherein: Ab is an antibody that binds to ROR1, comprising: (i) a variable heavy chain region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR2 Petition 870260064342, dated 06 / 30 / 2026, page.102 / 120 5 / 7 comprising the amino acid sequence of SEQ ID NO: 6 and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 7, and (ii) a variable light chain region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 9 and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 10; the ligand / payload has the structure: wherein the number of ligand / payload fractions per antibody is 1 to 7, the immunoconjugate is administered to the patient at a dose of 0.25 to 4.00 mg / kg, and (i) wherein the immunoconjugate is administered in three-week cycles and administered on day 1 of each cycle at said dose; (ii) wherein the immunoconjugate is administered in three-week cycles and administered on days 1 and 8 of each cycle at said dose; or (ii i) where the immunoconjugate is administered in four-week cycles and given on days 1, 8 and 15 of each cycle at the said dose.

13. Use according to claim 3, characterized in that the dose is 1.75, 2.00, 2.25, 2.50, 2.75 or 3.00 mg / kg.

14. Use of one or more immunoconjugate(s) of Formula (I): Petition 870260064342, dated 06 / 30 / 2026, page 103 / 120 6 / 7 (I), comprising an antibody conjugated to a ligand / payload, wherein: Ab is an antibody that binds to ROR1, comprising: (i) a variable heavy chain region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6 and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 7, and (ii) a variable light chain region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 8, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 9 and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 10;the linker / payload has the following structure: characterized in that it is for the manufacture of a pharmaceutical composition for treating hematologic cancer in a patient, wherein the number of linker / payload fractions per antibody is from 1 to 7; wherein the average number of linker / payload fractions bound to each antibody for all immunoconjugates in the pharmaceutical composition is from about 1 to about 7; wherein the pharmaceutical composition is formulated to provide a dose of 0.25 to 4.00 mg / kg; and (i) wherein the pharmaceutical composition is formulated to be administered in three-week cycles and administered on day 1 of each cycle at said dose; Petition 870260064342, dated 06 / 30 / 2026, p. 104 / 120 7 / 7 (ii) wherein the pharmaceutical composition is formulated to be administered in three-week cycles and administered on days 1 and 8 of each cycle at said dose;or (ii i) wherein the pharmaceutical composition is formulated to be administered in four-week cycles and administered on days 1, 8 and 15 of each cycle at the said dose.; 15. Use according to claim 14, characterized in that the average number of ligand / payload fractions attached to each antibody for all immunoconjugates present in the pharmaceutical composition is 3 to 5.

16. Invention of a product, process, system, kit or use, characterized by the fact that it comprises one or more elements described in this patent application.

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