Anti-GD2 regimen

Abstract

The present invention relates to administration of GD2-binding antibodies associated with side effects. In particular, the present invention relates to a method for reducing side effects associated with administration of GD2-binding antibodies.

Description

[Technical field]

[0001] The present invention relates to the administration of GD2-binding antibodies associated with side effects. In particular, the present invention relates to a method for reducing the side effects associated with the administration of GD2-binding antibodies. [Background technology]

[0002] Ganglioside GD2-binding antibodies have been found to be promising immunotherapeutic agents against GD2-expressing tumors such as neuroblastoma. GD2 expression in normal human tissues is restricted to skin melanocytes, neurons and peripheral nerve fibers, and the high expression of GD2 in neuroblastoma makes GD2 a tumor-associated antigen suitable for immunotherapy. The use of GD2-binding antibodies mediates tumor cell death via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

[0003] In the publication "Pathogenesis of the neurotoxicity caused by anti-GD2 antibody therapy", Journal of the Neurological Sciences, Vol. 149, August 1, 1997, pp. 127-130, Yuki et al. reported side effects associated with administration of an anti-GD2 MAb (14G2a).

[0004] Despite the promising antitumor effects induced by immunotherapy using GD2 antibodies, a substantial toxicity burden has been recognized. Patients undergoing GD2 antibody treatment have experienced severe adverse effects, including intense pain, fever, allergic reactions, blood pressure fluctuations, and neurotoxicity (Blom, Thomas et al., "Treatment-Related Toxicities During Anti-GD2 Immunotherapy in High-Risk Neuroblastoma Patients," Frontiers in oncology vol. 10 601076, 17 February 2021, doi:10.3389 / fonc.2020.601076). Blom et al. conducted a non-systematic literature review of the toxicity associated with anti-GD2 antibody immunotherapy in high-risk neuroblastoma patients. The immunotherapy protocol consisted of 17.5 mg / m2 per day administered intravenously over a 10-hour period for 4 consecutive days. 2 or 20 mg / m per day by constant-rate infusion over 8 hours for 5 consecutive days. 2 The most common adverse effects observed were pain, fever, cough, edema, and liver enzyme abnormalities.

[0005] In the publication, "Humanized 3F8 Anti-GD2 Monoclonal Antibody Dosing with Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Resistant Neuroblastoma A Phase 1 Clinical Trial," JAMA Oncology, Vol. 4, September 20, 2018, pp. 1729-1735, Kushner et al. conducted a phase 1 clinical trial using a 3+3 dose escalation design for the administration of hu3F8. Each cycle consisted of 250 μg / m 2 / d of GM-CSF, followed by 500 μg / m on days 1–5. 2Treatment consisted of administration of increasing doses of GM-CSF at 100 mg / d. hu3F8 was administered intravenously at a constant rate over 30 minutes on days 1, 3, and 5. Patients were premedicated with opiates and antihistamines to limit adverse effects.

[0006] In the publication, "A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma," Clinical Cancer Research, Vol. 25, November 2019, Furman et al. investigate the combination of the GD2 antibody hu14.18K322A with induction chemotherapy and the response and outcomes in children with newly diagnosed neuroblastoma. hu14.18K322A was administered in 4 daily doses on days 2-5 during each induction chemotherapy. The dose of hu14.18K322A was 40 mg / m per dose. 2 Each dose of hu14.18K322A was scheduled to be administered over 4 hours, although depending on patient tolerance, administration of hu14.18K322A was extended to 8 or 16 hours in some patients. Patients also received a 30-minute continuous infusion of a standard dose of an anesthetic agent such as morphine, hydromorphone, or fentanyl prior to administration of hu14.18K322A. Each course was followed by a 250 mg / m 2 Subcutaneous administration of GM-CSF was continued daily. Adverse effects noted included pain, hypotension, cough, and hypoxia.

[0007] In the publication, "A Pilot Trial of Hu14.18-IL2 (EMD 273063) in Subjects with Completely Resectable Recurrent Stage III or Stage IV Melanoma", Cancer Immunology Immunotherapy, Vol. 67, October 2018, pp. 1647-1658, Albertini et al. conducted a phase I clinical trial testing adjuvant hu14.18-IL2 in melanoma patients. Patients received hu14.18-IL2 on days 1, 2, and 3. The daily dose administered was 6 mg / m 2 / day, with each dose administered intravenously at a continuous rate over 4 hours. Adverse effects of hu14.18-IL2 treatment noted were hypotension, pain, and increases in bilirubin and creatinine.

[0008] In the publication "Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors", Journal of Clinical Oncology, Vol. 12, Jan. 1, 1994, pp. 184-193, Murray et al. investigated the toxicity and maximum tolerated dose of 14G2a in patients with neuroectodermal tumors such as melanoma, neuroblastoma or osteosarcoma. Patients were administered 50, 100 or 200 mg / m 2 Patients received 14G2a / day intravenously over 24 hours for 5 days. Toxicity and adverse effects of chronic 14G2a administration consisted of hypotension, pain, hyponatremia, fever, and rash. Murray et al. concluded that "Mab 14G2a has modest antitumor activity at the cost of significant toxicity."

[0009] Adverse effects such as pain, fever, rash and capillary leak syndrome are most likely due to increased production of inflammatory peptides. Severe adverse effects limit the dose of GD2 antibody that can be administered. The optimal administration schedule and timing remain to be determined (Navid, Fariba et al., "Anti-GD2 antibody therapy for GD2-expressing tumors," Current cancer drug targets vol. 10, 2 (2010): pp. 200-9). [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] "Pathogenesis of the neurotoxicity caused by anti-GD2 antibody therapy", Journal of the Neurological Sciences, Vol. 149, August 1, 1997, pp. 127-130, Yuki et al. [Non-Patent Document 2] Blom, Thomas et al., "Treatment-Related Toxicities During Anti-GD2 Immunotherapy in High-Risk Neuroblastoma Patients," Frontiers in oncology Volume 10, 601076, February 17, 2021, doi:10.3389 / fonc.2020.601076 [Non-Patent Document 3] "Humanized 3F8 Anti-GD2 Monoclonal Antibody Dosing with Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Resistant Neuroblastoma A Phase 1 Clinical Trial," JAMA Oncology, Vol. 4, September 20, 2018, pp. 1729-1735, Kushner et al. [Non-Patent Document 4] "A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma," Clinical Cancer Research, Vol. 25, November 2019, Furman et al. [Non-Patent Document 5] "A Pilot Trial of Hu14.18-IL2 (EMD 273063) in Subjects with Completely Resectable Recurrent Stage III or Stage IV Melanoma", Cancer Immunology Immunotherapy, Vol. 67, October 2018, pp. 1647-1658, Albertini et al. [Non-Patent Document 6] "Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors," Journal of Clinical Oncology, Vol. 12, January 1, 1994, pp. 184-193, Murray et al. [Non-Patent Document 7] Navid, Fariba et al., "Anti-GD2 antibody therapy for GD2-expressing tumors," Current cancer drug targets, Vol. 10, No. 2 (2010): pp. 200-9 Summary of the Invention [Problem to be solved by the invention]

[0011] Summary of the Invention Administration of GD2 antibodies causes severe adverse effects, especially pain, hypotension and / or hypoxia. Specifically, intravenous administration of anti-ganglioside GD2 monoclonal antibodies to humans causes pain, whether murine derived 3F8 and 14.G2a, chimeric ch14.18 (dinutuximab or dinutuximab beta), or humanized (naxitamab or hu14.18K322A). This pain remains the major drawback of anti-GD2 therapy and the major dose-limiting toxicity in the development of all anti-GD2 antibodies. The pain is usually severe, diffuse and mostly visceral, and the mechanism remains unclear. In part due to the side effects of pain and the therapeutic drugs given to patients, anti-GD2 antibody infusion commonly causes hypotension, tachycardia, urticaria, fever, bronchospasm, coughing, vomiting and nausea.

[0012] Known adverse events are summarized in Table 1.

[0013] [Table 1]

[0014] Adverse effects can be treated with premedication of opiates and steroids to reduce pain and inflammation, and antihistamines to reduce the risk of anaphylaxis. Alternatively, administration of GD2 antibodies is extended using very long infusion times to reduce (but not eliminate) adverse effects, which is not ideal for patients who must endure very long infusion times as a result. Reduction of complement activation using the K322A mutation also failed to eliminate pain, as patients continued to require significant amounts of anesthetics for pain management (Phase I Trial of a Novel Anti-GD22 Monoclonal Antibody, Hu14.18K322A, Designed to Decrease Toxicity in Children With Refractory or Recurrent Neuroblastoma, J.Clin.Oncol.32:1445-1452, 2014).

[0015] Thus, there is a need for improved dosing regimens for GD2 antibodies that reduce adverse reactions and do not require excessively long infusion times.

[0016] Anti-GD2 antibodies cause major side effects including pain, hypotension and hypoxia, which are significant management challenges, especially in young children. These side effects are electrophysiological, when sensory neurons are activated via antibody binding. Based on clinical signs and symptoms, as well as electrophysiological studies (described below), these side effects are likely mediated via the Autonomous Nervous System. It is also known that most small unmyelinated C fibers in the human body belong to the Autonomic Nervous System, while Aα-, Aβ- or Aδ-fibers are primarily considered to be part of the Somatic Nervous System.

[0017] The inventors performed experiments using confocal microscopy on tissue samples from healthy subjects, in which the GD2 antigen was fluorescently labeled. The GD2 antigen is found primarily in the perineurium and endoneurium of peripheral nerves, including the vagus nerve, the most prominent nerve of the autonomic nervous system.

[0018] Anti-GD2 experiments in rat models have shown that unmyelinated C-fiber nerves are the ones primarily activated by anti-GD2 antibodies. In the human body, unmyelinated C-fiber nerves belong mostly to the autonomic nervous system, most notably the vagus nerve.

[0019] Without wishing to be bound by theory, considering the location of pain (visceral), the timing of pain onset (within 30 minutes of antibody infusion), systemic effects (tachycardia, hypotension), rare organ damage (including nerves), ineffectiveness of opioids or α2δ calcium channel blockers (gabapentin or neurontin), and the absence of pathological evidence of immune neuritis, a possible explanation for the side effects of anti-GD2 antibodies is activation of the autonomic nervous system via the vagus nerve. If the infusion of anti-GD2 antibodies is slowed, the side effects of pain may decrease, but often persist. If the antibody infusion is given for more than 30 minutes up to an hour, the side effects become severe. However, shortly after antibody infusion, the side effects dissipate despite the continued presence of anti-GD2 antibodies circulating in the blood. This is consistent with the phenomenon of tachyphylaxis, in which electrical firing from neurons becomes increasingly slowed by activation until they stop firing completely. To reproduce tachyphylaxis, anti-GD2 antibodies are given in a dose-escalating fashion, starting with a low dose sufficient to fire the most sensitive but still few neurons, followed by more doses to fire the neurons in the next layer but still few, until the majority of neurons are slowed down before the full dose of antibody is given. The benefits provided by the methods described in this invention are not limited to the specific example of anti-GD2 antibodies, but apply equally to any antibody, protein or chemical with similar binding and neuronal activation properties, such as 3F8, hu3F8 (naxitamab), 14G2a, ch14.18 (dinutuximab, dinutuximab beta), hu14.18-K322A, hu14.18-IL2, hu3F8-BsAb (nivatrotamab and hu3F8-SADA.

[0020] The attending physician can determine the suitable dose-dependency according to the actual situation. Typically, the total daily dose is determined based on the patient's body weight or body surface area.

[0021] The total daily dose of the GD2 antibody to be administered can be calculated using the following formula: Dose (mg / day) = Dose (mg / kg / day) × Body weight (kg), or Administered dose (mg / day) = Dose (mg / m 2 / day) x body surface area (m 2 ).

[0022] Naxitamab was a GD2 antibody recently approved by the FDA under the name DANYELZA. According to the FDA approved package level, it is recommended that administration of naxitamab to 24-month-old infants with different weights may be performed according to the doses and injection volumes illustrated in Table 2, considering that the recommended dose is 3 mg / kg / day and the dose of each vial is 4 mg / mL.

[0023] [Table 2]

[0024] Body surface area (BSA) can be estimated based on height (cm) and weight (kg) using the Mosteller equation:

[0025]

number

[0026] Examples of BSA for 24-month-old infants with different weights and heights are illustrated in Table 3:

[0027] [Table 3] [Means for solving the problem]

[0028] The present invention provides a GD2 antibody dosing regimen that consists of a preferably stepwise increase in the rate of administration, resulting in a reduction in adverse effects, particularly infusion reactions, such as pain and hypotension, as well as a reduction in the requirement for premedication to manage adverse effects, and the need for nurses and physicians to manage patient safety during administration.

[0029] According to one aspect, the present invention provides a method of treatment and / or diagnosis comprising administration to a subject of a dosage of a GD2 binding antibody, comprising at least: i. administering an antibody at a first dosage rate for a first time, followed by: ii. administering the antibody at a second administration rate for a second time, the second administration rate being faster than the first administration rate. The present invention relates to a method comprising the steps of:

[0030] According to another aspect, the present invention relates to an antibody for use in the method of treatment according to the present invention.

[0031] According to another aspect, the present invention relates to a GD2 binding antibody or a fragment thereof for use in the method of treatment according to the present invention.

[0032] According to another aspect, the present invention relates to a pharmaceutical composition comprising the antibody for use in the method of treatment according to the present invention.

[0033] According to another aspect, the present invention relates to the use of an antibody for the manufacture of a pharmaceutical composition according to the invention.

[0034] According to another aspect, the present invention provides a method for producing a method for manufacturing a pharmaceutical composition comprising: i. administering a GD2 binding antibody at a first dosage rate for a first time, followed by: ii. administering a GD2 binding antibody at a second administration rate for a second time period, the second administration rate being faster than the first administration rate. The present invention relates to a GD2 binding antibody for use in a method of treatment comprising the steps of:

[0035] According to another aspect, the invention relates to a GD2 binding antibody for use in a method of treatment or a method of diagnosis comprising administering to a subject a dosage amount of the GD2 binding antibody, the method comprising: i. administering an antibody at a first dosage rate for a first time, followed by: ii. administering the antibody at a second administration rate for a second time, the second administration rate being faster than the first administration rate; the first administration rate is less than 1 mg / kg / h; The first period is at least five minutes long; The total administration time for the dose is 6 hours or less, preferably 4 hours or less. , concerning GD2 binding antibodies.

[0036] Additionally, intervention aspects of the invention are provided in the independent claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] According to one embodiment, the present invention relates to a method of treatment and / or diagnosis comprising administration to a subject of a dosage of a GD2 binding antibody, comprising at least: i. administering an antibody at a first dose rate for a first time, followed by: ii. administering the antibody at a second administration rate for a second time, the second administration rate being faster than the first administration rate. The present invention relates to a method comprising the steps of:

[0038] According to one embodiment, the invention relates to a method for treating a human subject with a condition treatable by a GD2 binding antibody.

[0039] According to one embodiment, the invention relates to a method according to the invention for the diagnosis of a condition associated with increased GD2 expression.

[0040] According to one embodiment, the invention relates to a method according to the invention, wherein the administration is performed by injection.

[0041] According to one embodiment, the present invention relates to a method in which the first administration rate is high enough to allow at least a portion of the nerves throughout the body to be stimulated, but low enough to substantially avoid unwanted side effects.

[0042] According to one embodiment, the present invention relates to a method in which the first administration rate is high enough to allow sympathetic stimulation, but low enough to substantially avoid unwanted side effects.

[0043] According to one embodiment, the invention relates to a method, wherein the first administration rate is high enough to allow at least a portion of the receptors that bind to the antibody to be saturated, but low enough to substantially avoid side effects.

[0044] According to one embodiment, the invention relates to a method in which an antibody interacts with a nerve, such as a sympathetic nerve.

[0045] According to one embodiment, the present invention relates to a method, wherein the GD2 binding antibody is a complete antibody consisting of two heavy chains and two light chains, a bispecific antibody, a SADA construct, an antibody fragment selected from F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc., or a chimeric and / or recombinant construct comprising a GD2 binding site.

[0046] According to one embodiment, the invention relates to a method, wherein the GD2 binding antibody is an immunocytokine, such as hu14.18-IL2.

[0047] According to one embodiment, the present invention relates to a method, wherein the GD2 binding antibody is humanized.

[0048] According to one embodiment, the invention relates to a method, wherein the GD2 binding antibody comprises the CDR sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10.

[0049] According to one embodiment, the invention relates to a method, wherein the GD2 binding antibody comprises the VH sequence of SEQ ID NO:3 and the VL sequence of SEQ ID NO:4.

[0050] According to one embodiment, the invention relates to a method, wherein the GD2 binding antibody comprises the heavy chain sequence of SEQ ID NO:1 and the light chain sequence of SEQ ID NO:2.

[0051] According to one embodiment, the invention relates to a method, wherein the GD2 binding antibody is a SADA construct, preferably comprising the sequence of SEQ ID NO:11.

[0052] According to one embodiment, the invention relates to a method, wherein the GD2 binding antibody is dinutuximab and comprises the sequence of SEQ ID NO: 12 and the sequence of SEQ ID NO: 13 and / or comprises the CDR sequences of dinutuximab.

[0053] According to one embodiment, the present invention relates to a method for the treatment or amelioration of cancer.

[0054] According to one embodiment, the invention relates to a method, wherein the cancer is selected from the group consisting of neuroblastoma, melanoma, osteosarcoma, sarcoma, brain tumor, small cell lung cancer, retinoblastoma, thyroid cancer, breast cancer or carcinoma.

[0055] According to one embodiment, the invention relates to a method, wherein the cancer is selected from osteosarcoma, liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, spindle cell sarcoma, brain tumor, small cell lung cancer, retinoblastoma, HTLV-1 infected T-cell leukemia, triple negative breast cancer and other GD2 positive tumors.

[0056] According to one embodiment, the invention relates to a method in which the number of adverse reactions of grade G3 or G4 is reduced compared to a situation in which a full dose of a GD2 binding antibody is administered at a constant rate at a time corresponding to time 1+2.

[0057] According to one embodiment, the present invention relates to a method, wherein the number of adverse reactions of grade G3 or G4 is reduced by at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, or the number of adverse reactions of grades G3 and G4 is practically non-existent.

[0058] According to one embodiment, the present invention relates to a method, where the rate of administration is increased gradually, continuously or stepwise during the total time of administration.

[0059] According to one embodiment, the invention relates to a method, wherein the total time of administration of the dose is 4 hours or less, and the amount of antibody administered in the first 15 minutes of administration is 5% or less, preferably 4% or less, more preferably 3% or less, preferably 2% or less of the total amount of antibody.

[0060] According to one embodiment, the invention relates to a method, wherein the total time of administration of the dose is 4 hours or less, and the amount of antibody administered in the first 30 minutes of administration is 10% or less, preferably 8% or less, more preferably 6% or less of the total amount of antibody.

[0061] According to one embodiment, the invention relates to a method, wherein the total time of administration of the dose is 4 hours or less, and the amount of antibody administered in the first 45 minutes of administration is 30% or less, preferably 20% or less, more preferably 15% or less of the total amount of antibody.

[0062] According to one embodiment, the invention relates to a method, wherein no more than 10% of the total amount of antibody is administered in the first 15%, more preferably the first 20%, preferably the first 25%, more preferably the first 30%, preferably the first 33% of the total time of administration of the dose.

[0063] According to one embodiment, the invention relates to a method, wherein no more than 33% of the total amount of antibody is administered in the first 50%, more preferably the first 55%, preferably the first 60%, more preferably the first 65%, preferably the first 70% of the total time of administration of the dose.

[0064] According to one embodiment, the invention relates to a method, wherein at least 50% of the total amount of antibody is administered in the last 40%, more preferably in the last 35%, preferably in the last 30%, more preferably in the last 25%, preferably in the last 20% of the total time of administration of the dose.

[0065] According to one embodiment, the invention relates to a method, wherein at least 66% of the total amount of antibody is administered in the last 50%, more preferably in the last 45%, preferably in the last 40%, more preferably in the last 35%, preferably in the last 33% of the total time of administration of the dose.

[0066] According to one embodiment, the invention relates to a method, wherein the treatment is carried out in two or more cycles, each cycle comprising administration of the GD2 antibody on two or more days, each cycle lasting for seven days.

[0067] According to one embodiment, the invention relates to a method, wherein the treatment is carried out in two or more cycles, each cycle comprising administration of the GD2 antibody on two or more days, the two administration days being separated by one day without antibody administration, and the two cycles being separated by at least two days without antibody administration.

[0068] According to one embodiment, the invention relates to a method, wherein each cycle comprises administration of the antibody over three days.

[0069] According to one embodiment, the invention relates to a method, wherein administration of the dose is followed by at least two days without antibody administration.

[0070] According to one embodiment, the present invention relates to a method in which no more than 20% of the total dose is administered in the first 75 minutes of administration.

[0071] According to one embodiment, the present invention relates to a method, wherein at least 80% of the total dose is administered in the last 60 minutes of administration.

[0072] According to one embodiment, the present invention provides a method for administering an antibody by infusion, the infusion rate being one of the following stages:

[0073] [Table 4] This relates to the method of adjusting within.

[0074] According to one embodiment, the invention relates to a method wherein the antibody is administered by infusion, the infusion rate is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the rate of the invention, and the infusion is continued until administration of the dose is completed.

[0075] According to one embodiment, the invention relates to a method wherein the antibody is administered by infusion, the infusion rate is adjusted to a rate according to the invention, the infusion time is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the infusion time according to the invention, and the infusion is continued until administration of the dose is completed.

[0076] According to one embodiment, the present invention provides a method for administering an antibody by injection, the antibody being administered in the following doses:

[0077] [Table 5] The present invention relates to a method for administering the same to a subject.

[0078] According to one embodiment, the invention relates to a method wherein the antibody is administered by infusion, the dose is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the dose of the invention, and the infusion is continued until administration of the dose is completed.

[0079] According to one embodiment, the invention relates to a method wherein an antibody is administered by infusion, the dose is adjusted to a dose of the invention, the infusion time is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the infusion time of the invention, and the infusion is continued until administration of the dose is completed.

[0080] According to one embodiment, the invention relates to a method, wherein the administration of the dose occurs within 2 days of the prior administration of the antibody.

[0081] According to one embodiment, the present invention relates to a method in which no more than 20% of the total dose is administered in the first 45 minutes of administration.

[0082] According to one embodiment, the present invention relates to a method, wherein at least 70% of the total dose is administered in the last 30 minutes of administration.

[0083] According to one embodiment, the present invention provides a method for administering an antibody by infusion, the infusion rate being:

[0084] [Table 6] This relates to the method of adjusting within.

[0085] According to one embodiment, the invention relates to a method wherein the antibody is administered by infusion, the infusion rate is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the rate of the invention, and the infusion is continued until administration of the dose is completed.

[0086] According to one embodiment, the invention relates to a method wherein the antibody is administered by infusion, the infusion rate is adjusted to a rate according to the invention, the infusion time is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the infusion time according to the invention, and the infusion is continued until administration of the dose is completed.

[0087] According to one embodiment, the present invention provides a method for administering an antibody by injection, the antibody being administered in the following doses:

[0088] [Table 7] The present invention relates to a method for administering the same to a subject.

[0089] According to one embodiment, the invention relates to a method wherein the antibody is administered by infusion, the dose is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the dose of the invention, and the infusion is continued until administration of the dose is completed.

[0090] According to one embodiment, the invention relates to a method wherein an antibody is administered by infusion, the dose is adjusted to a dose of the invention, the infusion time is adjusted to ±90%, more preferably ±80%, preferably ±70%, more preferably ±60%, preferably ±50%, more preferably ±40%, preferably ±30%, more preferably ±20%, preferably ±10% of the infusion time of the invention, and the infusion is continued until administration of the dose is completed.

[0091] According to one embodiment, the invention relates to a method, wherein the antibody is administered by infusion, and the infusion rate is adjusted according to the invention.

[0092] According to one embodiment, the invention relates to a method, wherein the antibody is administered by injection, the dose being administered according to the invention.

[0093] According to one embodiment, the present invention relates to a method, wherein the total time of administration is 7 hours or less, preferably 6 hours or less, more preferably 5 hours or less, preferably 4 hours or less, more preferably 3.5 hours or less, preferably 3 hours or less, more preferably 2.5 hours or less.

[0094] According to one embodiment, the present invention relates to a method, wherein the total time of administration is greater than 60 minutes, preferably greater than 70 minutes, more preferably greater than 75 minutes, preferably greater than 80 minutes, more preferably greater than 85 minutes.

[0095] According to one embodiment, the invention relates to a method, wherein the concentration of the antibody administered in step i is lower than the concentration of the antibody administered in step ii.

[0096] According to one embodiment, the invention relates to a method, wherein the first period of time continues until the level of neural stimulation is reduced.

[0097] According to one embodiment, the present invention relates to a method, wherein the first period is at least 30 minutes, more preferably 45 minutes, preferably 60 minutes, more preferably 75 minutes, preferably at least 120 minutes.

[0098] According to one embodiment, the present invention relates to a method in which the dosage administered in step i is 0.5-50% w / w, 1-20% w / w, preferably 2-15% w / w, more preferably 3-12% w / w, preferably 4-10% w / w, more preferably 5-8% w / w, preferably 6% w / w of the total dosage.

[0099] According to one embodiment, the present invention relates to a method, wherein the first administration rate is selected such that the dose administered in step i is 0.5-50% w / w, 1-20% w / w, preferably 2-15% w / w, more preferably 3-12% w / w, preferably 4-10% w / w, more preferably 5-8% w / w, preferably 6% w / w of the total dose.

[0100] According to one embodiment, the present invention relates to a method, wherein the first administration rate is less than 1 mg / kg / h.

[0101] According to one embodiment, the present invention relates to a method, wherein the first administration rate is selected from the range of 0.05 to 1 mg / kg / h, preferably 0.1 to 0.5 mg / kg / h, preferably approximately 0.3 mg / kg / h.

[0102] According to one embodiment, the present invention relates to a method, wherein the first period of time is greater than 60 minutes, preferably in the range of 60 to 120 minutes, preferably in the range of 60 to 90 minutes, most preferably around 75 minutes.

[0103] According to one embodiment, the invention relates to a method, wherein the second administration rate is maintained until administration of the dose is complete.

[0104] According to one embodiment, the present invention relates to a method, wherein the second period of time is equal to or less than 15 minutes, more preferably 30 minutes, preferably 45 minutes, more preferably 60 minutes, preferably 90 minutes.

[0105] According to one embodiment, the present invention relates to a method, wherein the second administration rate is selected such that the dose administered in step ii is at least 80% of the total dose administered, preferably at least 90% of the total dose, most preferably approximately 94% of the total dose.

[0106] According to one embodiment, the present invention relates to a method, wherein the second administration rate is greater than 1 mg / kg / h, preferably in the range of 1-5 mg / kg / h, most preferably approximately 4 mg / kg / h.

[0107] According to one embodiment, the present invention relates to a method, wherein the second period of time is greater than or equal to 15 minutes, preferably in the range of 15 to 30 minutes.

[0108] According to one embodiment, the invention relates to a method, wherein a total amount of a GD2 binding antibody is administered in steps i and ii.

[0109] According to one embodiment, the present invention relates to a method, wherein the total administered dose of GD2 binding antibody is in the range of 50-150 mg.

[0110] According to one embodiment, the invention relates to a method wherein the GD2 binding antibody is naxitamab, the first time period is 75 minutes, and the first administration rate is selected such that 6% of the total administered dose of the GD2 binding antibody is administered in step i, and the remainder of the total administered dose is administered by infusion in step ii.

[0111] According to one embodiment, the invention relates to a method according to the invention further comprising an interruption between steps i and ii.

[0112] According to one embodiment, the present invention relates to a method, wherein the subject of administration is a human or animal subject.

[0113] According to one embodiment, the present invention relates to a method, wherein the subject of administration is an adult, a juvenile or a child.

[0114] According to one embodiment, the present invention relates to an antibody for use in the method of treatment according to the present invention.

[0115] According to one embodiment, the present invention relates to a GD2 binding antibody or fragment thereof for use in the method of treatment according to the present invention.

[0116] According to one embodiment, the present invention relates to a pharmaceutical composition comprising the antibody for use in the method of treatment according to the present invention.

[0117] According to one embodiment, the present invention relates to a pharmaceutical composition according to the present invention comprising an excipient, binder or diluent.

[0118] According to one embodiment, the present invention relates to the use of an antibody for the manufacture of a pharmaceutical composition according to the present invention.

[0119] According to one embodiment, the present invention comprises: i. administering a GD2 binding antibody at a first dosage rate for a first time, followed by: ii. administering a GD2 binding antibody at a second administration rate for a second time period, the second administration rate being faster than the first administration rate. The present invention relates to a GD2 binding antibody for use in a method of treatment comprising the steps of:

[0120] According to one embodiment, the invention relates to a GD2 binding antibody for use in a method of treatment or a method of diagnosis comprising administering to a subject a dose of the GD2 binding antibody, the method comprising: i. administering an antibody at a first dose rate for a first time, followed by: ii. administering the antibody at a second administration rate for a second time, the second administration rate being faster than the first administration rate; the first administration rate is less than 1 mg / kg / h; The first period is at least five minutes long; The total administration time for the dose is 6 hours or less, preferably 4 hours or less. , concerning GD2 binding antibodies.

[0121] According to one embodiment, the invention relates to a GD2 binding antibody of the invention, wherein the method is for the treatment or amelioration of a condition in a subject, the condition being affected by administration of the antibody.

[0122] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the first administration rate is high enough to allow systemic nerves to be stimulated, but low enough to substantially avoid unwanted side effects.

[0123] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the first administration rate is high enough to allow the receptors to be saturated, but low enough to substantially avoid side effects.

[0124] According to one embodiment, the present invention relates to a GD2 binding antibody according to the present invention, in which the number of adverse reactions of grade G3 or G4 is reduced compared to a situation in which a full dose of the GD2 binding antibody is administered at a constant rate at a time corresponding to time 1+time 2.

[0125] According to one embodiment, the present invention relates to a GD2 binding antibody of the present invention, in which the number of adverse reactions of grade G3 or G4 is reduced by at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, or in which the number of adverse reactions of grades G3 and G4 is practically non-existent.

[0126] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the method comprises the treatment of cancer.

[0127] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the method of diagnosis or method of treatment is a method for diagnosing or treating cancer.

[0128] According to one embodiment, the invention relates to a GD2 binding antibody of the invention, wherein the cancer is selected from the group consisting of neuroblastoma, melanoma, sarcoma, brain tumor, breast cancer or carcinoma.

[0129] According to one embodiment, the invention relates to a GD2 binding antibody of the invention, wherein the cancer is selected from osteosarcoma, liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, spindle cell sarcoma, brain tumor, small cell lung cancer, retinoblastoma, HTLV-1 infected T cell leukemia, triple negative breast cancer and other GD2 positive tumors.

[0130] According to one embodiment, the present invention relates to a GD2 binding antibody according to the present invention which is a complete antibody consisting of two heavy chains and two light chains, a bispecific antibody, a SADA construct, an antibody fragment selected from F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc., or a chimeric and / or recombinant construct comprising a GD2 binding site.

[0131] According to one embodiment, the present invention relates to a GD2 binding antibody according to the invention which is an immunocytokine.

[0132] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, which is humanized.

[0133] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention comprising the CDR sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10.

[0134] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, comprising a VH sequence according to SEQ ID NO:3 and a VL sequence according to SEQ ID NO:4.

[0135] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, comprising the heavy chain sequence of SEQ ID NO:1 and the light chain sequence of SEQ ID NO:2.

[0136] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, comprising the sequence SEQ ID NO:11.

[0137] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the first administration is performed by injection.

[0138] According to one embodiment, the present invention relates to a GD2 binding antibody according to the present invention, wherein the dosage administered in step i is 0.5-50% w / w, 1-20% w / w, preferably 2-15% w / w, more preferably 3-12% w / w, preferably 4-10% w / w, more preferably 5-8% w / w, preferably 6% w / w of the total dosage.

[0139] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the first administration rate is selected such that the dose administered in step i is 0.5-50% w / w, 1-20% w / w, preferably 2-15% w / w, more preferably 3-12% w / w, preferably 4-10% w / w, more preferably 5-8% w / w, preferably 6% w / w of the total dose.

[0140] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the first administration rate is less than 250 μg / min.

[0141] According to one embodiment, the present invention relates to a GD2 binding antibody according to the present invention, wherein the first administration rate is selected from the range of 50 to 250 μg / min, preferably 75 to 200 μg / min, preferably 100 to 150 μg / min, and is preferably approximately 120 μg / min.

[0142] According to one embodiment, the present invention relates to a GD2 binding antibody according to the present invention, wherein the first time period is at least 10 minutes, preferably at least 15 minutes, more preferably at least 30 minutes, preferably at least 45 minutes, more preferably at least 45 minutes, preferably at least 60 minutes.

[0143] According to one embodiment, the present invention relates to a GD2 binding antibody according to the present invention, wherein the first administration rate is selected from the range of 0.05 to 1 mg / kg / h, preferably 0.1 to 0.5 mg / kg / h, and is preferably approximately 0.3 mg / kg / h.

[0144] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the first period is longer than 60 minutes, preferably in the range of 60 to 120 minutes, preferably in the range of 60 to 90 minutes, most preferably approximately 75 minutes.

[0145] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the second time administration is performed by injection.

[0146] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the second administration rate is selected such that the dose administered in step ii is at least 80% of the total dose administered, preferably at least 90% of the total dose, most preferably approximately 94% of the total dose.

[0147] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the second administration rate is greater than 1 mg / min, preferably in the range of 1 to 25 mg / min, preferably in the range of 5 to 15 mg / min, most preferably approximately 10 mg / min.

[0148] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the second administration rate is greater than 1 mg / kg / h, preferably in the range of 1-10 mg / kg / h, most preferably approximately 4-6 mg / kg / h.

[0149] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the second period of time is equal to or less than 15 minutes, more preferably 30 minutes, preferably 45 minutes, more preferably 60 minutes, preferably 90 minutes.

[0150] According to one embodiment, the present invention relates to a GD2 binding antibody according to the invention, wherein the second period of time is greater than or equal to 15 minutes, preferably in the range of 15 to 30 minutes.

[0151] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein a total amount of the GD2 binding antibody is administered in steps i and ii.

[0152] According to one embodiment, the present invention relates to a GD2 binding antibody according to the invention, wherein the total administered dose of the GD2 binding antibody is in the range of 50-150 mg.

[0153] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the GD2 binding antibody is naxitamab, the first time period is 75 minutes and the first administration rate is selected such that 6% of the total administered dose of the GD2 binding antibody is administered in step i and the remainder of the total administered dose is administered by infusion in step ii.

[0154] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, further comprising an interruption between steps i and ii.

[0155] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, the dosage of which is less than or equal to 3 mg / kg.

[0156] According to one embodiment, the present invention relates to a method for administering an antibody by infusion, the infusion rate being: A) Within the following stages:

[0157] [Table 8] or B) one of the following stages:

[0158] [Table 9] The present invention relates to a GD2-binding antibody prepared by any one of the following methods.

[0159] According to one embodiment, the present invention relates to a method for administering an antibody by injection, the dose being: A) The following steps:

[0160] [Table 10] or B) the following steps:

[0161] [Table 11] The present invention relates to a GD2 binding antibody according to the present invention, which is administered in either one of the following ways:

[0162] According to one embodiment, the invention relates to a GD2 binding antibody according to the invention, wherein the subject is an adult, juvenile or pediatric subject.

[0163] Embodiments of the inventive intervention are provided in the claims.

[0164] According to one embodiment, the present invention may relate to the Self-Assembly and Dis-Assembly (SADA) technology, first described in the International Patent Application with Publication Number WO 2018 / 204873, which is incorporated herein by reference. This technology is based on SADA domains, which are small polypeptides that have, among other things, concentration-dependent self-assembly and disassembly properties. In some embodiments, the SADA polypeptide is or comprises a tetramerization domain of p53, p63, p73, hnRNPC, SNAP-23, Stefin B, KCNQ4, CBFA2T1, or any other examples of such polypeptides provided, without limitation, in the International Patent Application.

[0165] According to one embodiment, the present invention may relate to a SADA complex, according to the present specification, intended to mean a polypeptide comprising a SADA domain and at least one additional domain.

[0166] According to one embodiment, the invention may relate to a SADA complex which comprises a GD2 binding site.

[0167] definition Adverse events Adverse events associated with administration of the GD2 antibodies of the present disclosure may be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) published on August 9, 2006 by the Department of Clinical Trials, NCI, NIH, and DHHS.

[0168] Grades refer to the severity of the adverse effect. The CTCAE uses a unique clinical description of the severity of each AE based on general guidelines, grades 1 to 5: Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening or disabling AE; Grade 5: death-related AE.

[0169] Antibody or antibody fragment An antibody fragment is a portion of an antibody, such as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc. Regardless of structure, an antibody fragment binds to the same antigen recognized by the intact antibody. For example, the 3F8 monoclonal antibody fragment binds to the epitope recognized by 3F8. The term "antibody fragment" also includes any synthetic or engineered protein that acts like an antibody by binding to a specific antigen to form a complex. For example, antibody fragments include isolated fragments consisting of variable regions, such as "Fv" fragments consisting of the variable regions of heavy and light chains, recombinant single chain polypeptide molecules in which the light and heavy variable regions are connected by a peptide linker ("scFv protein"), and minimal recognition units consisting of amino acid residues that mimic the hypervariable region.

[0170] antibody The term "antibody" is an art-recognized term and is intended to include molecules or active fragments of molecules that bind to known antigens. Examples of active fragments of molecules that bind to known antigens include Fab and F(ab')2 fragments. These active fragments can be derived from the antibodies of the present invention by several techniques. For example, purified monoclonal antibodies can be cleaved with an enzyme such as pepsin and subjected to HPLC (high performance liquid chromatography) gel filtration. Appropriate fractions containing Fab fragments can then be collected and concentrated by membrane filtration or the like. The term "antibody" also includes bispecific and chimeric antibodies, as well as other available formats.

[0171] GD2 antibody The term GD2 antibody is intended to mean an antibody or antibody fragment capable of binding to GD2. GD2 antibodies may also be referred to as anti-GD2 antibodies or anti-GD2 binding sites, and these terms are used interchangeably within the present application and claims.

[0172] antibody fragment An antibody fragment is a portion of an antibody, such as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc. Regardless of structure, an antibody fragment binds to the same antigen recognized by the intact antibody. For example, the 3F8 monoclonal antibody fragment binds to the epitope recognized by 3F8. The term "antibody fragment" also includes any synthetic or engineered protein that acts like an antibody by binding to a specific antigen to form a complex. For example, antibody fragments include isolated fragments consisting of variable regions, such as "Fv" fragments consisting of the variable regions of heavy and light chains, recombinant single chain polypeptide molecules in which the light and heavy variable regions are connected by a peptide linker ("scFv protein"), and minimal recognition units consisting of amino acid residues that mimic the hypervariable region.

[0173] bispecific antibody Bispecific antibodies are antibodies that can simultaneously bind to two targets that are of different structures. Bispecific antibodies (bsAb) and bispecific antibody fragments (bsFab) have at least one arm that specifically binds to an antigen, e.g., GD2, and at least one other arm that specifically binds to another antigen, e.g., a targetable conjugate carrying a therapeutic or diagnostic agent. A variety of bispecific fusion proteins can be produced using molecular engineering. In one form, the bispecific fusion protein is bivalent, e.g., consisting of an scFv with a single binding site for one antigen and a Fab fragment with a single binding site for a second antigen. In another form, the bispecific fusion protein is tetravalent, e.g., consisting of an IgG with two binding sites for one antigen and two identical scFvs for a second antigen.

[0174] CDR Complementarity determining regions (CDRs) are parts of the variable region of an antibody and are of major importance for the binding specificity of the antibody. A typical antibody, consisting of two heavy and two light chains, has six CDR sequences, three in the light chain and three in the heavy chain.

[0175] Chimeric antibodies Chimeric antibodies are recombinant proteins that contain the variable regions, including the complementarity determining regions (CDRs), of an antibody derived from one species, e.g., a rodent antibody, while the constant domains of the antibody molecule are derived from a human antibody. The constant domains of the chimeric antibody may be derived from another species, e.g., cat or dog.

[0176] Humanized antibodies A humanized antibody is a recombinant protein in which the CDRs of an antibody derived from one species, such as a rodent antibody, have been transferred from the heavy and light variable chains of the rodent antibody to human heavy and light variable domains. The constant domains of the antibody molecule are derived from a human antibody.

[0177] Human antibodies may be antibodies obtained from transgenic mice that have been "engineered" to specifically produce human antibodies in response to antigenic challenge. In this technique, elements of the human heavy and light chain loci are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy and light chain loci. The transgenic mice are capable of synthesizing human antibodies specific to human antigens, and the mice can be used to produce human antibody-secreting hybridomas.

[0178] Immunocytokines Immunocytokines are fusion proteins that contain a cytokine portion fused to a monoclonal antibody or antibody fragment.

[0179] speed The term "rate" is used as a measure of how quickly a substance is administered or delivered to a subject. Thus, rate is generally expressed as the amount delivered per unit of time, for example, a GD2 antibody may be administered to a patient at a rate measured in μg per hour.

[0180] Rates may also be expressed as amounts per unit of time in units of body weight or body surface area of ​​the patient being treated to account for differences in the size of the patient being treated. Examples include mg / kg / h or mg / m 2 / h is one example.

[0181] subject "Subject" or "individual" or "animal" or "patient" or "mammal" means any subject for which diagnosis, prognosis, or treatment is desired, particularly a mammalian subject. Mammalian subjects include humans and other primates, domestic animals, farm animals, and zoo, racing, or pet animals, such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, bulls, cows, and the like.

[0182] treatment As used herein, the terms "treatment", "treat", "treated" or "treating" refer to prophylaxis and / or therapy, particularly where the progression of an undesirable physiological change or disorder in a subject, such as multiple sclerosis, should be prevented or slowed (alleviated). Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, a stable (i.e., not worsening) state of disease, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonged survival compared to expected survival in the absence of treatment. Those in need of treatment include those already with the condition or disease, as well as those prone to have the condition or disorder, or those in whom the condition or disease is to be prevented.

[0183] Pharmaceutical Compositions As used herein, the term "pharmaceutical composition" is intended to mean a composition for administering a drug or medicine to a patient in need thereof. Pharmaceutical compositions are prepared from pharmaceutical grade ingredients using methods and techniques known in the pharmaceutical or pharmacological field, for example as described in the European Pharmacopoeia, 10th edition.

[0184] SADA Self-assembly and disassembly (SADA) technology, first disclosed in WO 2018 / 204873, exploits the SADA domain, which has concentration-dependent assembly and disassembly properties. Complexes containing SADA domains typically exist in at least two distinct forms, a tetrameric form at high concentrations and a monomeric form at low concentrations. [Brief description of the drawings]

[0185] [Figure 1] Figure 1 shows the results of confocal microscopy on tissue samples of the vagus nerve, from which it is concluded that the GD2 antigen is found primarily in connection with unmyelinated C-fibers (gray area). [Diagram 2] 1 shows the results of electrophysiological analysis of the sweat response upon GD2 antibody (naxitamab) infusion on day 1. The sweat response decreases over time as a result of successive infusions of the GD2 antibody. [Diagram 3] 1 shows the GD2 antibody dosing rate and total infusion time for Model A compared to the constant rate dosing on Day 1. [Figure 4] 1 shows the GD2 antibody dosing rate and total infusion time for model B compared to the constant rate dosing on days 3 and 5, respectively. [Diagram 5] The GD2 antibody dose administered at each stage on day 1 of Model A and the total infusion time from the start of infusion are shown. [Figure 6] The GD2 antibody dose administered at each stage on days 3 and 5, respectively, of Model B and the total infusion time from the start of infusion are shown. [Figure 7]Figure 1 shows the cumulative dose administered and total infusion time on day 1 for Model A compared to a constant rate administration. In Model A, each data point represents the cumulative dose of GD2 binding antibody at a particular time point. The total time of administration of the total dose is 4 hours or less. [Figure 8] Shown are the cumulative dose administered and total infusion time on days 3 and 5 of model B compared to a constant rate administration. In model B, each data point represents a cumulative dose of GD2 binding antibody at a particular time point. The total time of administration of the total dose is 4 hours or less. All cited references are incorporated by reference.

[0186] The accompanying figures and examples are provided to illustrate, not to limit, the present invention. It will be apparent to one skilled in the art that the aspects, embodiments and any claims of the present invention may be combined.

[0187] All percentages are on a weight / weight basis unless otherwise stated. All measurements are made at standard conditions (ambient temperature and pressure) unless otherwise stated. Test conditions comply with European Pharmacopoeia 8.0 unless otherwise stated. EXAMPLES

[0188] Materials and Methods GD2 antibody: naxitamab, commercially available as DANYELZA (Y-mAbs Therapeutics Inc, NY; USA)

[0189] Example 1: Confocal microscopy method The inventors performed anatomical (confocal microscopy) analysis on primary human tissues and on neuroblastoma patients to localize the GD2 antigen in these tissues.

[0190] Anti-GD2 monoclonal antibodies were stained with green fluorescent dye and applied to the tissues, after which the samples were visualized using confocal microscopy.

[0191] result Confocal microscopy of peripheral nerves from the autonomic nervous system of neonatal human autopsies found GD2 expression in endoneurial Schwann cells but not in neuronal axons (see Figure 1). Expression levels were estimated to be approximately four-fold lower than GD2 expression in neuroblastoma tumor cells.

[0192] [Example 2] Electrophysiological analysis Electrophysiological analysis of autonomic nervous system responses was measured during GD2 antibody infusion in neuroblastoma patients. Patients were treated with several cycles of GD2 antibody infusion, each cycle consisting of infusions on days 1 (Monday), 3 (Wednesday), and 5 (Friday).

[0193] In this example, electrophysiological analysis was performed during the infusion on day 1 of the cycle.

[0194] method: Electrophysiological (sympathetic skin response (SSR)) analyses performed on primary human tissues and neuroblastoma patients demonstrated that activation of the autonomic nervous system is the underlying cause of most adverse events suffered upon administration of GD2 antibody.

[0195] SSR was used to measure sweating and cardiovascular components of autonomic nervous system activation, and action potentials were analyzed for latency and amplitude following sympathetic stimulation.

[0196] SSR was performed to assess unmyelinated axon function of the autonomic nervous system.

[0197] For measurement of electrodermal activity after sympathetic nerve stimulation by surface electromyography, electrodes were placed on the patient's palms or soles (sol) and a reference electrode was placed.

[0198] Baseline responses were recorded, the infusion of GD2 was started, and the measured responses were recorded at the time of complete infusion (see FIG. 2).

[0199] result: In all cases, responses showed short latencies and low amplitudes immediately following the onset of the infusion.

[0200] The response progressively diminishes until it disappears completely some time after treatment begins.

[0201] The reaction never recovered after 45 minutes of treatment.

[0202] [Example 3] Electrophysiological analysis The experiment disclosed in Example 2 was repeated with the infusion performed on day 5 of the cycle.

[0203] Results showed an initial low amplitude and a rapid loss of response.

[0204] [Example 4] Incremental Protocol A new protocol for infusion of GD2 antibody was developed and tested in 20 patients.

[0205] According to the protocol, patients were treated in cycles including infusions of GD2 antibody on days 1 (Monday), 3 (Wednesday) and 5 (Friday).

[0206] On day 1, the following injection scheme was used (see Figures 3, 5, 7 and Table 4).

[0207] [Table 12]

[0208] On days 3 and 5, the following injection scheme was used (see Figures 4, 6, 8 and Table 5).

[0209] [Table 13]

[0210] The titration protocol was tested in 20 patients for a total of 53 cycles and 159 infusions. Three patients (15%) experienced grade 3 or 4 adverse events (hypertension, apnea, and pain). This protocol allowed for a reduced level of monitoring required and did not require bedside attendance by an MD.

[0211] This had to be compared with the commonly applied constant rate infusion (FIGS. 7 and 8) and applied in the clinical trial Study 201, where grade 3 or 4 pain was experienced by 72% of patients.

[0212] array Naxitamab sequence:

[0213] [ka] TIFF2024546660000017.tif228161TIFF2024546660000018.tif216161

Claims

1. A composition comprising a GD2-binding antibody for use in a method of treatment and / or a method of diagnosis, the method comprising: i. administering the GD2 binding antibody at a first administration rate for a first time period, followed by: ii. administering the GD2 binding antibody at a second administration rate for a second time period, wherein the second administration rate is faster than the first administration rate; the first and / or second administration is performed by infusion; and the first administration rate is less than 1 mg / kg / h; the first period is at least 5 minutes; and The total administration time of the dose is 6 hours or less. , a composition comprising a GD2-binding antibody.

2. A composition comprising a GD2-binding antibody for use as described in claim 1, wherein the treatment and / or diagnosis is for treating or diagnosing cancer.

3. 3. The composition comprising a GD2 binding antibody for use according to claim 2, wherein the cancer is selected from the group consisting of neuroblastoma, melanoma, sarcoma, brain tumor, breast cancer or carcinoma.

4. 3. The composition comprising a GD2-binding antibody for use according to claim 2, wherein the cancer is selected from osteosarcoma, liposarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, spindle cell sarcoma, brain tumor, small cell lung cancer, retinoblastoma, HTLV-1-infected T-cell leukemia, and triple-negative breast cancer.

5. The GD2-binding antibody i. CDR sequences of SEQ ID NOs: 5, 6, 7, 8, 9 and 10 ii. the VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 4, and / or iii. The heavy chain sequence of SEQ ID NO: 1 and the light chain sequence of SEQ ID NO: 2 2. A composition comprising a GD2-binding antibody for use according to claim 1, comprising:

6. 2. A composition comprising a GD2-binding antibody for use according to claim 1, wherein the dose administered in step i is 0.5-50% w / w, 1-20% w / w, 2-15% w / w, 3-12% w / w, 4-10% w / w, 5-8% w / w, or 6% w / w of the total dose, and / or the second administration rate is selected such that the dose administered in step ii is at least 80% of the total dose administered, at least 90% of the total dose, or approximately 94% of the total dose.

7. 2. A composition comprising a GD2-binding antibody for use according to claim 1, wherein the first administration rate is selected from the range of 50 to 250 μg / min, 75 to 200 μg / min, 100 to 150 μg / min, or is approximately 120 μg / min, and / or the second administration rate is greater than 1 mg / min, in the range of 1 to 25 mg / min, in the range of 5 to 15 mg / min, or is approximately 10 mg / min.

8. A composition comprising a GD2-binding antibody for use as described in claim 1, wherein the first administration rate is selected from the range of 0.05 to 1 mg / kg / h, 0.1 to 0.5 mg / kg / h, or is approximately 0.3 mg / kg / h, and / or the second administration rate is greater than 1 mg / min, in the range of 1 to 25 mg / min, in the range of 5 to 15 mg / min, or approximately 10 mg / min.

9. A composition comprising a GD2-binding antibody for use as described in claim 1, wherein the first time period is at least 10 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 45 minutes, at least 60 minutes, more than 60 minutes, in the range of 60 to 120 minutes, in the range of 60 to 90 minutes, or approximately 75 minutes; and / or the second time period is 15 minutes or less, 30 minutes, 45 minutes, 60 minutes, or 90 minutes.

10. 2. A composition comprising the GD2 binding antibody of claim 1, wherein the total administered dose of the GD2 binding antibody is in the range of 50-150 mg, and / or the dose is 3 mg / kg or less.

11. 2. A composition comprising a GD2 binding antibody for use according to claim 1, wherein the GD2 binding antibody is naxitamab, the first time period is 75 minutes, and the first administration rate is selected such that 6% of the total administered dose of the GD2 binding antibody is administered in step i, and the remainder of the total administered dose is administered by infusion in step ii.

12. 2. A composition comprising a GD2-binding antibody for use according to claim 1, further comprising an interruption between steps i and ii.

13. The antibody is administered by infusion, and the infusion rate is: A) Of the following steps: Table 1 or B) one of the following steps: Table 2 and / or the dose is adjusted by A) The following steps: Table 3 or B) the following steps: Table 4 2. A composition comprising a GD2-binding antibody for use according to claim 1, wherein the composition is administered in one of the following ways:

14. 2. A composition comprising a GD2 binding antibody for use according to claim 1, wherein the subject is a human adult, juvenile or child.

15. A composition comprising a GD2-binding antibody for use according to any of claims 1 to 14, wherein the number of adverse reactions of grade G3 or G4 as defined using the Common Terminology Criteria for Adverse Events (CTCAE) is reduced by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% at the time corresponding to said first time plus said second time compared to a situation in which the full dose of the GD2-binding antibody is administered at a constant rate, or the number of adverse reactions of grade G3 and G4 is virtually non-existent.

16. A composition comprising a GD2-binding antibody for use as described in claim 1, wherein the total administration time of the dose is 4 hours or less.

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