Use of an Anti-P-selectin Antibody

Abstract

The invention relates to a method of treating priapism in a patient in need of such treatment, comprising administering a pharmaceutically effective amount of an anti-P-selectin antibody or a binding fragment thereof to said patient, especially wherein the patient is suffering from Sickle Cell Disease (SCD), and related invention embodiments (uses, methods, pharmaceutical preparations and use in the preparation of pharmaceutical preparations).

Claims

1. A method of treating priapism in a patient in need of such treatment, comprising administering a pharmaceutically effective amount of an anti-P-selectin antibody or a binding fragment thereof to said patient.

2. The method according to claim 1, wherein the patient is suffering from Sickle Cell Disease (SCD).

3. The method according to claim 1, wherein the anti-P-selectin antibody is crizanlizumab or a binding fragment thereof.

4. The method according to claim 1, wherein the patient receives co-treatment with hydroxyurea, hydroxycarbamide, L-glutamine, Erythropoietin-stimulating agents, acetylsalicylic acid, nonsteroidal anti-inflammatory drug, leuprolide, or anticoagulants at prophylactic doses, or any combination of two or more thereof.

5. The method according to claim 3, wherein the patient receives co-treatment with hydroxyurea, hydroxycarbamide, L-glutamine, Erythropoietin-stimulating agents, acetylsalicylic acid, nonsteroidal anti-inflammatory drug, leuprolide, or anticoagulants at prophylactic doses, or any combination of two or more thereof.

6. The method of claim 1 wherein the treatment is administered as monotherapy.

7. The method according to claim 3 wherein the treatment is administered as monotherapy with crizanlizumab.

8. The method according to claim 3, wherein crizanlizumab or a binding fragment thereof, is administered 5 mg/kg or 7.5 mg/kg per treatment.

9. The method of claim 3, wherein crizanlizumab or a binding fragment thereof, is administered 5 mg/kg or 7.5 mg/kg monthly.

10. The method of claim 3, wherein crizanlizumab or a binding fragment thereof, is administered in a loading dose followed by a maintenance dose.

11. The method according to claim 10, wherein the loading dose is 5 mg/kg or 7.5 mg/kg and is administered twice in a time interval of 2 weeks+/−3 days, and the maintenance dosage is then administered 4 weeks+/−3 days after the second loading dose administration and then at regular intervals of 4 weeks+/−3 days.

12. The method according to claim 1, where the priapism treated is defined as an unwanted or painful penile erection lasting at least 60 minutes.

13. The method according to claim 3, where the priapism treated is defined as an unwanted penile erection lasting at least 60 minutes.

14. The method according to claim 8, where the priapism treated is defined as an unwanted penile erection lasting at least 60 minutes.

15. The method according to claim 1, wherein the treatment is a monotherapy with crizanlizumab.

16. The method according to claim 1, where the anti-P-Selectin antibody or binding fragment thereof comprises a heavy chain variable region comprising three CDRs comprising, consisting essentially of or consisting of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively and a light chain variable region comprising three CDRs comprising, consisting essentially of or consisting of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively.

Description

EXAMPLES

Example 1: Treatment of a Patient Suffering from Priapism with Crizanlizumab

[0144] In the SUSTAIN (placebo controlled Phase 2) trial (Ataga K I, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 2017; 376:429-39. DOI: 10.1056/NEJMoa1611770) Treatment of SCD patients with crizanlizumab at 5.0 mg/kg demonstrated statistically significant, clinically meaningful efficacy results versus placebo in reduction of annual rate of VOCs leading to healthcare visit and delay in onset of VOCs.

[0145] Following completion of the SUSTAIN trial, one subject stayed presented frequent priapism about three times a week. After a formal approval, the subject was re-initiated with crizanlizumab seven months after his last treatment in the SUSTAIN trial. By May 17, 2019, the patient has maintained total control of crisis and disappearance of the occurrence of priapism and pain crisis since re-initiation of crizanlizumab. To this date (June 2019) this subject continues to receive crizanlizumab.

[0146] The subject has been on the medication till now (May 2020) and had no crisis during the entire period.

Example 2: A Prospective Phase II, Open-Label, Single-Arm, Multicenter, Study to Assess Efficacy and Safety of SEG101 (Crizanlizumab), in Sickle Cell Disease Patients with Priapism (SPARTAN)

[0147] Preclinical studies in transgenic mice have shown that SCD promotes an increased P-selectin expression in several vascular beds of various organs (e.g. lung, heart, small bowel, large bowel, penis etc.). The penis is the only organ where the vascular bed exhibited an increased expression of both P- and E-selectin, which may be relevant to a SCD-related priapism. Although, priapism has been attributed to both ischemic and non-ischemic causes, vaso-occlusion-induced ischemia is now generally thought to account for the priapism associated with SCD.

[0148] The purpose of this study is to evaluate the effect of crizanlizumab on priapic events in sickle cell disease patients with a history of priapism. We collect data for 26 weeks prior to the treatment phase to create a baseline for priapic events (defined as an event of an unwanted painful erection lasting greater than 60 minutes), acute priapic events (which is defined as an event of an unwanted, painful erection lasting more than 4 hours), uncomplicated and complicated vaso-occlusive crisis (VOC), based on the hypothesis is crizanlizumab treatment reduces priapic events by at least 25% in SCD patients with priapism.

[0149] The Primary Objective is to evaluate the clinical efficacy (percent reduction from baseline) of crizanlizumab in SCD-related priapism.

[0150] Among the Secondary Objectives, the following are aimed at: [0151] To evaluate the clinical efficacy (rate of priapic events) of crizanlizumab in SCD-related priapism [0152] To evaluate the clinical efficacy of crizanlizumab in SCD-related acute priapism [0153] To evaluate the clinical efficacy of crizanlizumab for uncomplicated VOC (defined as an acute event of pain with no known cause for pain other than a vaso-occlusive event; and requiring treatment with a parenteral or oral opioids or other parenteral analgesic; but is NOT classified as an acute chest syndrome, hepatic sequestration, splenic sequestration or priapism and these events are not adjudicated). [0154] To evaluate the clinical efficacy of crizanlizumab in complicated VOCs (acute chest syndrome, hepatic sequestration, splenic sequestration, and especially acute priapism) [0155] To further assess the safety and tolerability of crizanlizumab

[0156] Among the Exploratory Objectives, the following are examined: [0157] To evaluate the clinical efficacy of crizanlizumab on leg ulcers (improve the severity indices for the leg ulcer based on depth by 26 and 52 weeks) [0158] To evaluate quality of life (measures of Quality of Life via a Priapism Impact Profile (PIP) tool [0159] Measure of healthcare resource utilization due to SCD events (e.g. number of ER visits, frequency and duration of hospitalization etc.) by 26 weeks and 52 weeks. [0160] To evaluate the clinical efficacy of crizanlizumab on penile fibrosis based on USG (UltrasonogrPHY) by 52 weeks.

Study Design

[0161] This is a multicenter, prospective, phase II, single-arm, open-label study to assess the efficacy and safety of crizanlizumab in SCD patients with priapism. A total of approximately 56 male subjects aged ≥16 years, who meet all of the inclusion criteria and none of the exclusion criteria are included in the study.

[0162] The baseline period is defined as 26 weeks consisting of 14 weeks pre-screening and 12 weeks screening. Eligible subjects are treated with crizanlizumab at a dose of 5.0 mg/kg. From the first screening visit until the end of follow-up, the total study duration is 79 weeks (including 12 weeks of screening, 52 weeks of treatment and 15 weeks of follow-up period). The primary analysis of the study is conducted by 26 weeks to assess efficacy of crizanlizumab in this patient population. The secondary and exploratory endpoints are assessed by 26 weeks and/or 52 weeks. Subjects are followed in the mandatory safety follow-up period until 105 days (15 weeks) after the last dosing.

Pre-Screening

[0163] Before participating in the study, information to determine key eligibility criteria is collected as a part of priapism medical history questionnaire.

Screening Phase

[0164] Eighty-four days (12 weeks) before start of treatment, written informed consent, according to local guidelines, is signed by the subjects and prior to any study related screening procedures are performed. During this period, subjects have 3 visits and be monitored for priapic events to determine their eligibility to the trial using an electronic reporting system. All screening evaluations must be performed during the screening period from Day −84 to Day −1.

[0165] At the first screening visit after signing the ICF (at Day 84), subjects are briefed about the study requirements, including the instruction on how to use the electronic device(s) required to record the priapic event(s) information. At the first screening visit, the prospective subjects are also asked about their prior medical history related to priapism. This information is collected via a priapism medical history questionnaire.

Treatment Phase

[0166] Once eligibility criteria have been confirmed by Novartis via the eligibility checklist, the subject receives investigational treatment. Subjects receive investigational treatment by IV infusion over 30 min on Week 1 Day 1, Week 3 Day 1, and then on Day 1 of every 4-week cycle.

[0167] Safety is monitored as below. Subjects receive investigational treatment for a maximum of 1 year (52 weeks) or until unacceptable toxicity, death, lost to follow-up or discontinued from the study treatment for any other reasons prior to 52 weeks. Following the treatment discontinuation, subjects perform an End of Treatment visit.

Population

[0168] A total of 56 male patients with SCD-related priapism aged ≥16 years is recruited across the United States. To be considered for this study, patients must have had ≥4 priapic events during the 14 weeks prior to screening and having at least 3 priapic events during the 12 week screening period with at least 1 event occurring within 4 weeks prior to the first treatment.

Key Inclusion Criteria

[0169] Subjects eligible for inclusion in this study must meet all of the following criteria:

[0170] 1. Signed informed consent and applicable adolescent assent and/or parental consent for adolescent subjects, obligatorily obtained prior to participation in the study

[0171] 2. Male patients aged 16 years and above

[0172] 3. Confirmed diagnosis of SCD by hemoglobin electrophoresis or high performance liquid chromatography. All SCD genotypes are eligible (HbSS, HbSβ0, HbSC, HbSβ+, and others)

[0173] 4. Patients who have experienced ≥4 priapic events (unwanted erection lasting at least 60 minutes) over 14 week pre-screening

[0174] 5. Patients who have experienced at least 3 priapic events (unwanted erection lasting at least 60 minutes) during the 12 week screening period with at least 1 event occurring within 4 weeks prior to the first treatment.

[0175] 6. If receiving hydroxyurea/hydroxycarbamide or L-glutamine or erythropoietin stimulating agent, must have been receiving the drug for at least 14 weeks prior to screening and plan to continue taking the drug at the same dose and schedule during the trial

[0176] 7. If receiving prophylactic treatment for priapism, must have been receiving the drug for at least 14 weeks prior to screening and plan to continue taking the drug at the same dose and schedule during the trial

[0177] 8. Adequate renal and hepatic function as defined: [0178] Glomerular filtration rate ≥45 mL/min/1.73 m2 calculated by CKD-EPI [0179] Alanine aminotransferase (ALT)≤3×ULN [0180] Direct (conjugated) bilirubin ≤2×ULN

[0181] 9. Patient must meet the following laboratory values at the screening visit: [0182] Absolute Neutrophil Count ≥1.0×109/L [0183] Hemoglobin >4.0 g/dL [0184] Platelets ≥75×109/L

Key Exclusion Criteria

[0185] Following are the key exclusion criteria:

[0186] 1. Patients who have penile prosthetic implants or shunts or any other surgical procedure on the penis

[0187] 2. Patients who have taken drugs/medications that may induce priapism (as per Appendix 5) over the 14 weeks pre-screening period

[0188] 3. Patients who have received leuprolide acetate (Lupron) within 3 months before pre-screening.

[0189] 4. Patients who had an erection lasting more than 12 hours over the 14 week pre-screening period

[0190] 5. Patients who had an erection lasting more than 12 hours during the 12 weeks of the screening period

[0191] 6. History of severe hypersensitivity reaction to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction

[0192] 7. Contraindication or hypersensitivity to any drug or metabolites from similar class as study drug or to any excipients of the study drug formulation

[0193] 8. Use of therapeutic anticoagulants (prophylactic doses permitted) or antiplatelet therapy (other than aspirin or NSAIDs) within the 10 days prior to Week 1 Day 1 dosing. Note: prophylactic anticoagulant dose is permitted, as per local guidelines

[0194] 9. Received a monoclonal antibody or immunomodulatory agent within 1 year of screening, or has documented immunogenicity to a prior biologic

[0195] 10. Patient with any severe reaction to crizanlizumab, or discontinued crizanlizumab due to an AE

[0196] 11. Patients should not be receiving another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to Screening or plans to participate in another investigational drug trial

[0197] 12. Resting QTcF≥470 msec at pretreatment (baseline) or inability to determine QTc

[0198] 13. Cardiac or cardiac repolarization abnormality, including any of the following: [0199] History of myocardial infarction, angina pectoris, coronary artery bypass graft, or uncontrolled congestive heart failure within 6 months prior to starting study treatment [0200] Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block)

[0201] 14. Current drug or alcohol abuse: [0202] has a positive qualitative urine drug test at screening for cocaine, phencyclidine, or amphetamines [0203] consumes >12 (for males) standard alcoholic beverages per week

[0204] 15. Any documented history of a clinical stroke or intracranial hemorrhage, or an uninvestigated neurologic finding within the past 12 months before screening. Silent infarct only present on imaging is allowed

[0205] 16. Clinically significant bleeding disorder

[0206] 17. Planning to undergo a major surgical procedure during the duration of the study

[0207] 18. Patient with active HIV infection (detectable viral load)

[0208] 19. Patients with active Hepatitis B infection (HBsAg positive)

[0209] Note: Patients with antecedent but no active Hepatitis B (i.e. anti-HBc positive, HBsAg and HBV-DNA negative) are eligible

[0210] 20. Patients with positive test for hepatitis C ribonucleic acid (HCV RNA)

[0211] Note: Patients in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or those that achieved a sustained virological response

Study Treatment

[0212] Crizanlizumab (SEG101) at 5.0 mg/kg

[0213] On infusion day, the pharmacist or designated personnel prepares individual doses of crizanlizumab for subjects on a milligram per kilogram basis in a 100 mL infusion bag of a sterile 0.9% sodium chloride solution (0.9% Sodium Chloride Injection, USP) in accordance with the Pharmacy Manual. Study drug is administered over 30 minutes by IV infusion.

[0214] If a subject experiences a IRRs, he may receive pre-medication on subsequent dosing days as per institutional standard of care, at the discretion of the treating physician.

[0215] If a subject experiences a Grade 3 or 4 IRRs, the subject discontinues

Concomitant Treatment

[0216] In general, the use of any concomitant medication/therapies deemed necessary for the care of the subject is permitted, except prohibited treatments. Hydroxy urea/Hydroxycarbamide or L-glutamine treatment is permitted if the subject has been prescribed any of these continuously over at least 14 weeks prior to the screening. The dosing should not be altered or terminated except for safety reasons. Erythropoietin-stimulating agents are also permitted to manage chronic symptomatic anemia with the same requirement for 6 months prior therapy. Aspirin, nonsteroidal anti-inflammatory drug (NSAIDs) and prophylactic doses (as per local guidelines) of anticoagulants are permitted, while other anti-platelets agents or anticoagulants at doses targeting therapeutic levels are prohibited. All approved forms of analgesia for pain are permitted per standard of care. Other approved medications for supportive care (antiemetics, anxiolytics, hypnotics, antihistamines) are permitted, including marinol (dronabinol).

[0217] Concomitant prophylactic treatment for SCD-related priapism is permitted provided the subject has been prescribed the same medication consistently for at least 14 weeks prior to screening as per inclusion criterion 7. Dosing should not be altered or terminated other than for safety during the duration of the study. In subjects not on prophylactic medications, treatment should not be initiated during the study. If a physician deems it necessary to terminate or alter treatment during the study, the monitor must be notified immediately to determine whether the subject may continue the study.

[0218] Although transfusion of cellular blood products is permitted, it is unclear how such transfusions would impact the PK/PD of crizanlizumab, so investigators are encouraged to obtain PK and PD samples before and after each transfusion session when possible. It should also be considered that the administration of products containing immunoglobulins (plasma, IVIG, anti-globulins) may also impact the efficacy of crizanlizumab, and optional PK and PD testing may also be performed prior to and following administration of such therapies. Although Endari™, the FDA-approved version of L-glutamine, is permitted, other over-the counter forms of L-glutamine are discouraged, as are other natural and herbal remedies (e.g. EvenFlo and/or products containing dang gui, Ligustrum root, ginseng root, white peony, corydalis, salvia, copodonosis, poria, jujube, Angelica sinensis, lovage) due the unproven efficacy and variable quality and composition of these products. Vitamin and mineral supplements (e.g. fish oil, folic acid, L-arginine, L-citrulline, magnesium, riboflavin, vitamin C, vitamin D, vitamin E, and zinc) are also permitted, though caution is advised when taking amounts exceeding 100% of the recommended daily allowance.

[0219] The use of other investigational drugs is prohibited during the study. In addition, the administration of monoclonal antibodies other than the investigational treatment is prohibited, due to the theoretical potential for cross-reactivity and/or overlapping toxicities with other monoclonal antibodies. If investigational agents or other monoclonal antibodies have been used in the past, they must have been discontinued at least 30 days or 5 half-lives of that agent, (whichever is greater) prior to the screening visit.

[0220] If a subject does not tolerate the protocol-specified dosing schedule, dose interruptions are either recommended or mandated in order to allow subjects to continue the study treatment until the next dose scheduled. Dose reductions are not allowed. If a subject experiences drug-induced toxicities, the subject should be closely monitored and a decision to continue or discontinue the subject from the study should be done at the next dose scheduled.

Efficacy Assessment

[0221] Following are the key primary and secondary planned efficacy assessments: [0222] Percent reduction in priapic events by 26 weeks of treatment [0223] The rate of priapic events by 26 and 52 weeks of treatment [0224] Percent reduction in acute priapic events by 26 and 52 weeks of treatment [0225] The rate of complicated/uncomplicated

[0226] Priapism is defined as an unwanted or painful penile erection lasting at least 60 minutes. The end of the priapic event is the duration when the unwanted erection has resolved. This event is self-reported via an electronic reporting system, and this data should be collected throughout the study period. Primary efficacy endpoint is assessed by evaluating the percent reduction in priapic events by 26 weeks.

[0227] Acute priapic events are defined as an unwanted, painful erection that lasts more than 4 hours and need a visit to emergency room. Management of ischemic priapism require an aggressive and stepwise procedures to achieve prompt resolution. Aspiration/irrigation, in combination with intracavernous injections of α-agonist is usually the first-line therapy. Penile blood aspiration involves using a transglanular intracorporal angiocatheter insertion or a proximal penile shaft needle access. The percent reduction in acute priapic events from baseline by 26 and 52 weeks of treatment is assessed.

Key Safety Assessments

[0228] Following are the key safety assessment for this study: [0229] Monitoring of AEs/SAEs [0230] Vital signs, Physical assessments [0231] Hematology, chemistry, coagulation, urinalysis, Hepatitis markers [0232] Presence of HIV Antibody (at screening only) [0233] Cardiac assessments: ECGs and echocardiogram

Other Assessments

[0234] Lower extremities examination for leg ulcer(s) [0235] Symptoms and quality-of-life measurement by using the patient reported outcomes tools ASCQ-Me and PIP [0236] Healthcare resource utilization (HRU) [0237] Optional ultrasonography assessment of penile fibrosis

Data Analysis

[0238] The primary endpoint of the study is the percent reduction from baseline inpriapic events by 26 weeks (i.e. up to pre-infusion Week 27, Day 1). Efficacy endpoints are analyzed using all FAS (Full Analysis Set) subjects who have completed treatment. It has been hypothesized that crizanlizumab treatment reduces the priapic events by at least 25% in SCD subjects with priapism.

[0239] Percent reduction from baseline in priapic events are tested using a nonparametric test (i.e. Wilcoxon's Sign Rank test) along with Hodges-Lehmann estimate of median percent reduction Number of priapic events and percent reduction from baseline by Week 26 are summarized descriptively.

[0240] Demonstration of significant percent reduction from baseline in priapic events is evaluated using the following hypothesis:

[0241] H0: p<0.25, where p is the percent reduction in priapic events by 26 weeks.

[0242] H1: p≥0.25, where p is the percent reduction in priapic events by 26 weeks.

[0243] If the above null hypothesis is rejected, significant reduction in priapic events is demonstrated statistically. Percent reduction from baseline in priapic events is tested using a nonparametric test (i.e. Wilcoxon's Sign Rank test). Hodges-Lehmann estimate of median percent reduction in priapic

[0244] events is also reported, along with corresponding 95% confidence intervals. The significance of the efficacy endpoints is assessed at α=0.05 level.

[0245] The primary analysis is performed on all FAS patients who have completed 26 weeks on treatment.

[0246] Number of priapic events is summarized at baseline and by Week 26, and percent reduction from baseline by Week 26 is summarized by mean, standard deviation, median, minimum and maximum. In addition, subgroup analysis of the primary endpoint is also performed based on the number of priapic events categories (i.e. 7-13, 14-21, ≥22) at baseline. The priapic events categories may be re-grouped to ensure that there is adequate number of subjects in each category for analysis. Additional analyses of the primary endpoint is also performed for the subgroups of subjects with stuttering and acute priapism. The FAS consists of all subjects to whom the study treatment has been assigned and who received at least 1 dose of a study treatment and have at least 1 post-baseline assessment.

[0247] As part of the supportive analysis, the primary analysis is repeated on all subjects in FAS. In addition the annualized rate of priapic events are summarized for all subjects in FAS that have completed treatment. Three additional supportive analyses are also performed, the total number of priapic episodes in the screening period (12 weeks baseline) is compared to the total number of priapic episodes occurring in the first 12 weeks on treatment (0-12 weeks) using a nonparametric test (i.e. Wilcoxon's Sign Rank test). A similar analysis is performed to compare to the total number of priapic episodes occurring in the last 12 weeks on treatment (15-26 weeks). Finally an analysis using a mixed effects regression model is performed using median event counts within prespecified time windows.

[0248] Similar analyses on percent reduction in acute priapic events for subjects is conducted, as was completed for primary end-point. Descriptive summary statistics are presented for the rate of events and number of priapic events at Baseline, by Week 26 and by Week 52. In addition the rate of uncomplicated VOC events and VOC events is summarized. Safety analyses is based on the safety analysis set. Adverse events are summarized by system organ class and or preferred term, seriousness, CTCAE (Common Terminology Criteria for Adverse events) grade based severity, type of adverse event, relation to study treatment. Other safety assessments (e.g. ECG, vital signs) are summarized by treatment group.

[0249] As of March 2020, four patients in the SPARTAN trial had undergone 10 weeks of treatment with crizanlizumab. Our preliminary findings are the following: [0250] Patient 1 baseline was 84 priapic episodes in 26 weeks (ca 3.2 episodes per week). At week 10 of treatment, the number of priapic episodes recorded for Patient 1 was 30 (ca 3 episodes per week), corresponding to a reduction of 7% in the frequency of priapic episodes. [0251] Patient 2 baseline was 173 priapic episodes in 26 weeks (ca 6.7 episodes per week). At week 10 of treatment, the number of priapic episodes recorded for Patient 2 was 50 (ca 5 episodes per week), corresponding to a reduction of 25% in the frequency of priapic episodes. [0252] Patient 3 baseline was 56 priapic episodes in 26 weeks (ca 2.2 episodes per week). At week 10 of treatment, the number of priapic episodes recorded for Patient 3 was 11 (ca 1.1 episodes per week), corresponding to a reduction of 49% in the frequency of priapic episodes. [0253] Patient 4 baseline was 10 priapic episodes in 26 weeks (ca 0.4 episodes per week). At week 10 of treatment, the number of priapic episodes recorded for Patient 4 was 2 (ca 0.2 episodes per week), corresponding to a reduction of 48% in the frequency of priapic episodes.

[0254] Based on these 4 patients, over the 10 weeks of treatment, the number of priapic episodes per patient per week went from 3.1 to 2.3 corresponding to a 25% reduction in the frequency of priapic episodes.

[0255] The results indicate efficiency of the treatment with crizanlizumab in the treatment of priapism in SCD patients.

TABLE-US-00001 Sequences SEQ ID NO: 1 P-selectin amino acid sequence WTYHYSTKAYSWNISRKYCQNRYTDLVAIQNKNEIDYLNKVLPYYSSYYWIGIRKNNKTWTWVGTKKALT NEAENWADNEPNNKRNNEDCVEIYIKSPSAPGKWNDEHCLKKKHALCYTASCQDMSCSKQGECLETIGNY TCSCYPGFYGPECEYVRECGELELPQHVLMNCSHPLGNFSFNSQCSFHCTDGYQVNGPSKLECLASGIWT NKPPQCLAAQCPPLKIPERGNMTCLHSAKAFQHQSSCSFSCEEGFALVGPEVVQCTASGVWTAPAPVCK SEQ ID NO: 2 CDR light chain amino acid sequence KASQSVDYDGHSYMN SEQ ID NO: 3 CDR light chain amino acid sequence AASNLES SEQ ID NO: 4 CDR light chain amino acid sequence QQSDENPLT SEQ ID NO: 5 Mature light chain variable region amino acid sequence DIQMTQSPSSLSASVGDRVTITCKASQSVDYDGHSYMNWYQQKPGKAPKLLIYAASNLESGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQSDENPLTFGGGTKVEIKR SEQ ID NO: 6 CDR heavy chain amino acid sequence SYDIN SEQ ID NO: 7 CDR heavy chain amino acid sequence WIYPGDGSIKYNEKFKG SEQ ID NO: 8 CDR heavy chain amino acid sequence RGEYGNYEGAMDY SEQ ID NO: 9 Mature heavy chain variable region amino acid sequence QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYDINWVRQAPGKGLEWMGWIYPGDGSIKYNEKFKGRVTM TVDKSTDTAYMELSSLRSEDTAVYYCARRGEYGNYEGAMDYWGQGTLVTVSS SEQ ID NO: 10 Human Kappa constant region amino acid sequence TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 11 IgG.sub.2 constant region amino acid sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVIC VVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAP IEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 12 Light chain mature amino acid sequence DIQMTQSPSSLSASVGDRVTITCKASQSVDYDGHSYMNWYQQKPGKAPKLLIYAASNLESGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQSDENPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC SEQ ID NO: 13 Heavy chain mature amino acid sequence QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYDINWVRQAPGKGLEWMGWIYPGDGSIKYNEKFKGRVTM TVDKSTDTAYMELSSLRSEDTAVYYCARRGEYGNYEGAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRST SESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHK PSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRIPEVTCVVVDVSHEDPEVQFNWYV DGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCAVSNKGLPAPIEKTISKTKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 14 Light chain complete amino acid sequence MESQTQVFVYMLLWLSGVDGDIQMTQSPSSLSASVGDRVTITCKASQSVDYDGHSYMNWYQQKPGKAPKL LIYAASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDENPLTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 15 Heavy chain complete amino acid sequence MKCSWVIFFLMAVVTGVNSQVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYDINWVRQAPGKGLEWMGWI YPGDGSIKYNEKFKGRVTMTVDKSTDTAYMELSSLRSEDTAVYYCARRGEYGNYEGAMDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCAVSNKGLPA PIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 18 Complete light variable region amino acid sequence MESQTQVFVYMLLWLSGVDGDIQMTQSPSSLSASVGDRVTITCKASQSVDYDGHSYMNWYQQKPGKAPKL LIYAASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDENPLTFGGGTKVEIKR SEQ ID NO: 19 Complete heavy variable region amino acid sequence MKCSWVIFFLMAVVTGVNSQVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYDINWVRQAPGKGLEWMGWI YPGDGSIKYNEKFKGRVTMTVDKSTDTAYMELSSLRSEDTAVYYCARRGEYGNYEGAMDYWGQGTLVTVS S SEQ ID NO: 23 IgG.sub.2 constant region amino acid sequence with a one amino acid residue mutation to reduce complement activation ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVIC VVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCAVSNKGLPAP IEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK