TW201718014A - Use of C5 inhibitors in Transplant Associated Microangiopathy - Google Patents

Abstract

The present invention relates to methods of using drugs, e.g. antibodies such as e.g. anti-C5 antibodies, that are capable of inhibiting the complement pathway for treating Transplant Associated Microangiopathy, in particular after hematopoietic cell transplantation.

Description

Use of C5 inhibitors in transplantation-related microangiopathy

Transplantation-associated microangiopathy (TAM; or transplant-associated thrombotic microangiopathy (TA-TMA)) may be a complication of allogeneic hematopoietic cell transplantation (HSCT). TAM is a secondary microangiopathy associated with whole body irradiation, high dose chemotherapy, viral reactivation, and the use of calcineurin inhibitors with rapamycin. TAM does not belong to other categories of thrombotic microangiopathy (TMA), namely atypical hemolytic uremic syndrome (aHUS) or thrombotic thrombocytopenic purpura (TTP) (Chapin et al. (2014) Clin Adv Hematol Oncol; 12(9): 565-73). The exact mechanism of TAM is not fully understood, but it is thought to involve initial complement activation and a C5-dependent effector mechanism, which also results in immunoglobulin consumption. Triggering appears to be endothelial cell damage leading to a prothrombotic state in the microvasculature. Depending on the area of the vascular bed involved, TAM can cause kidney, gastrointestinal and neurological insufficiency. TAM is associated with high morbidity and mortality, with some estimates of mortality associated with up to 80% (Chapin et al. 2014, supra). The involvement of complement is indicated by recent clinical data using the C5 targeting antibody eculizumab. Preliminary data indicate that 4 of the 6 individuals undergoing HSCT procedures have a beneficial response following administration of eculizumab (Jodele et al. (2014) Biol Blood Marrow Transplant; 20(4): 518-25). As of March 2015, 25 patients who have been treated with eculizumab have been reported to have a mix result. The positive response in published cases appears to be associated with low body weight, high doses by weight, and absence of severe acute graft-versus-host disease.

There is therefore a need for improved therapies for the treatment or prevention of TAM, especially when associated with cell transplantation, such as stem cell transplantation (TAM-SCT) or hematopoietic stem cell transplantation (TAM-HSCT).

The present invention relates to the use of a drug, such as an antibody such as an anti-C5 antibody capable of inhibiting the complement pathway, in a subject in need thereof after treatment (in detail after cell transplantation, such as post-transplantation (TAM-PCT) or hematopoietic precursor cells). Post-transplantation (TAM-HPCT) method for transplantation-related microangiopathy.

In particular, it relates to a particular dosage regimen for such C5 inhibitors, for example comprising a first induction phase, which in turn comprises a maintenance period, wherein the maintenance dose is optionally lower than the induction dose.

According to the invention, it is provided that:

1.1 A C5 inhibitor, such as an anti-C5 antibody, such as Coversin, for use in the prevention or treatment of transplant-associated microvascular disease (TAM) in a patient in need thereof, such as TAM after cell transplantation.

1.2 A C5 inhibitor as defined in 1.1, wherein the C5 inhibitor is administered at a dose of about 50 mg/kg (e.g., 20 mg/kg) or at a dose of from about 800 mg to about 2000 mg (e.g., from about 1000 mg to about 2000 mg). Needed patients.

1.3 A C5 inhibitor as defined in 1.1, wherein the C5 inhibitor is administered at a dose of about 30 mg/kg (e.g., 10 mg/kg) or at a dose of about 400 mg to about 1000 mg (e.g., about 500 mg to about 1000 mg). Needed patients.

1.4 A C5 inhibitor as defined in 1.1 to 1.3, wherein the C5 inhibitor is comprised A patient in need is administered between 1 week and 8 weeks, such as a 3 week or 4 week period.

1.5 A C5 inhibitor as defined in 1.1 to 1.3, wherein the C5 inhibitor is administered during a period of between 1 month and 11 months, for example 4 months or 5 months. patient.

1.6 A C5 inhibitor as defined in 1.1, 1.2 or 1.3, wherein the C5 inhibitor first doses the patient in need during the induction phase and then at a maintenance dose during the maintenance period, wherein The maintenance dose is lower than the induction dose.

1.7 A C5 inhibitor as defined under 1.6, wherein the inducing dose is about 50 mg/kg, such as 20 mg/kg; or a dose of from about 800 mg to about 2000 mg, such as from about 1000 mg to about 2000 mg.

1.8 A C5 inhibitor as defined under 1.6 or 1.7, wherein the induction phase comprises between 1 week and 8 weeks, such as 3 weeks or 4 weeks.

1.9 A C5 inhibitor as defined in 1.6 to 1.8, wherein the maintenance dose is about 30 mg/kg, such as 10 mg/kg; or a dose of from about 400 mg to about 1000 mg, such as from about 500 mg to about 1000 mg.

1.10 A C5 inhibitor as defined in 1.6 to 1.9, wherein the maintenance period comprises between 1 month and 11 months, such as 4 months or 5 months.

1.11 A C5 inhibitor as defined under 1.1 to 1.10, wherein the C5 inhibitor is administered weekly.

1.12 A C5 inhibitor as defined in 1.1 to 1.11, wherein the C5 inhibitor is administered until the hematological symptoms of TAM resolve.

1.13 A C5 inhibitor as defined in 1.1 to 1.12 for the prevention or treatment of TAM (TAM-PCT) after precursor cell transplantation or TAM after transplantation of hematopoietic precursor cells (TAM- HPCT) or TAM (TAM-HSCT) after allogeneic hematopoietic stem cell transplantation.

1.14 A C5 inhibitor as defined in 1.1 to 1.13, selected from the group consisting of tesidolumab, eculizumab, 305 variant antibody and homologous antibodies as defined herein For example, an antibody homologous to Tesdoruzumab, such as Tesdoruzumab.

2.1 A method for monitoring the efficacy of a treatment for TAM-PCT or TAM-HSCT or allogeneic TAM-HSCT in an individual who has been transplanted, such as HSCT, the method comprising the steps of: a. in a sample of the individual Total complement activity (CH50) is measured, and b. Tesdorumab is administered, for example, by a therapy as defined under any of 1.1 to 1.14.

2.2 A method for monitoring the efficacy of a treatment for TAM-PCT or TAM-HSCT or allogeneic TAM-HSCT in an individual who has been transplanted, such as HSCT, the method comprising the steps of: a. in a sample of the individual The total complement activity (CH50) is measured, and b. a C5 inhibitor, such as an anti-C5 antibody, is administered as described in any of 1.1 to 1.14.

2.3 A method for treating or preventing TAM (e.g., TAM after cell transplantation) comprising administering a therapeutic amount of a C5 inhibitor to a patient in need thereof according to a usage as defined in any one of 1.1 to 1.14.

2.4 A method for treating or preventing TAM (e.g., TAM after cell transplantation) comprising administering to a patient in need thereof a therapeutic amount of a tresotuzumab or a homologous antibody as defined herein.

2.5 The method as defined in any one of 2.1 to 2.4, wherein the C5 inhibitor is Kang A compound or anti-C5 antibody, for example, selected from the group consisting of Tesdoruzumab, Eculizumab, 305 variant antibody, and homologous antibodies as defined herein, for example, with Tesduzumab The antibody of the source is, for example, Tesduzumab.

3.1 Use of a C5 inhibitor (for example, an anti-C5 antibody) for the preparation of a medicament for preventing or treating TAM, such as TAM after cell transplantation, such as TAM (TAM-PCT) or hematopoietic precursor cells after precursor cell transplantation. Post-transplant TAM (TAM-HPCT) or TAM (TAM-HSCT) after allogeneic hematopoietic stem cell transplantation.

3.2 Use of a C5 inhibitor (eg, an anti-C5 antibody) for the manufacture of a medicament for the prophylaxis or treatment of TAM, wherein the C5 inhibitor (eg, an anti-C5 antibody) is administered according to a dose as defined under 1.2 to 1.12 above or The drug program is administered.

3.3 The use of a C5 inhibitor (such as a rehabilitative or anti-C5 antibody) for the preparation of a medicament as defined in 3.1 or 3.2 above, wherein the C5 inhibitor is selected from the group consisting of Tesdoruzumab as defined herein A group consisting of eculizumab, a 305 variant antibody, and a homologous antibody thereof, for example, an antibody homologous to Tesdoruzumab, such as Tesdorumab.

Figure 1 depicts a randomized, SoC control, open-label, multi-center study design design in patients with TAM after hematopoietic precursor cell transplantation (HPCT) from related or unrelated donors. The study consisted of: a screening period of up to 28 days; a treatment period of 16 weeks, which can be extended to a maximum of 45 weeks (without adequate inhibition of serum complement after 16 weeks); 36 weeks follow-up And at the end of the 52-week study visit (EOS).

Unless otherwise stated, the average person will understand the terminology according to conventional usage.

The term "about" or "approximately" means a specific value as determined by a person of ordinary skill. Within the accepted error range, it will depend in part on how the measurement or measurement is performed, such as the limitations of the measurement system. For example, "about" can mean within one or more than one standard deviation based on the practice in the art. Alternatively, "about" can mean up to 20%, or up to 10%, or up to 5%, or up to 1% of a given value. Alternatively, particularly in the context of a biological system or method, the term may mean within an order of magnitude of a certain value, preferably within 5 times and more preferably within 2 times. When a particular value is described in the scope of the application and the claims, the term "about" is intended to be within the acceptable tolerance of the particular value, unless otherwise stated.

As used herein, the term "treating" is intended to mean an individual having a condition as described herein administered to a composition for curing, ameliorating, alleviating, treating, preventing, or ameliorating the condition, the condition of the condition, the condition following The condition of the disease, or the predisposition to have it.

As used herein, the term "therapeutically effective amount" or "effective amount" means a pharmaceutical composition or method sufficient to exhibit a meaningful patient benefit (eg, to cure a chronic condition or an increase in the cure rate of such conditions, or a reduction in an abnormal condition). The total amount of each active ingredient. This includes both treatment and prophylaxis. Thus, such compounds can be used at very early stages of the disease, or prior to early onset, or after significant development. When applied to individual active ingredients administered separately, the term refers only to that ingredient.

The terms "individual", "host", "subject" and "patient" are used interchangeably to refer to an animal as a therapeutic, observational, and/or experimental target. Generally, the individual, host, individual or patient is a human, although other mammals are within the scope of the invention.

disease

As defined herein, TAM refers to a transplant-associated microangiopathy; it may also be referred to as a transplant-associated thrombotic microangiopathy (TA-TMA).

According to the invention, the target disease is TAM and in particular TAM after body transplantation (or as a complication thereof) or TAM after cell transplantation (or as a complication thereof), such as TAM after stem cell transplantation (TAM-SCT), for example TAM (TAM-PCT) after precursor cell transplantation, such as TAM (TAM-HPCT) after hematopoietic precursor cell transplantation, such as TAM (TAM-HSCT) after hematopoietic stem cell transplantation.

Cell transplantation herein refers to autologous cell transplantation (the donor is a patient receiving his or her own stem cells), or allogeneic cell transplantation (the patient receives stem cells from another body).

In particular, the present invention relates to individuals who have been transplanted, for example, cell transplantation, such as precursor or stem cell transplantation, such as hematopoietic precursor cell transplantation or hematopoietic stem cell transplantation, in particular HSCT, such as autologous or allogeneic HSCT.

Relevant risk factors in the retrospective study of TAM development after allogeneic HSCT include agents used during transplantation and infectious complications. Modulators including busulfan, fludarabine, cisplatin and radiation increase the risk of subsequent TAM-HSCT. Other agents commonly associated with TAM-HSCT are reported to include the calcineurin inhibitors tacrolimus and cyclosporine and the newer mammalian target of rapamycin (mTOR). ) inhibitors. Viral infection is often considered a "trigger" of TAM-HSCT, as patients exhibiting small vessel damage may also have concomitant infections such as CMV, adenovirus, parvovirus B19, HHV-6 and BK viruses.

combination

In one aspect, a medicament, such as an antibody (eg, an anti-C5 antibody), capable of inhibiting the complement pathway, is provided for use in treating an individual (in particular, an individual who has been subjected to a stem cell transplant or a hematopoietic stem cell transplant (eg, allogeneic HSCT)) Transplantation-related microvascular disease (TAM) after transplantation (eg, solid or cell transplantation) (or as a complication of transplantation), such as after precursor cell transplantation TAM (TAM-PCT) or TAM (TAM-SCT) after stem cell transplantation, such as TAM (TAM-HPCT) after hematopoietic precursor cell transplantation or TAM (TAM-HSCT) after hematopoietic stem cell transplantation.

In a particular aspect, the medicament may comprise a complement inhibitor, such as a renin or an antibody capable of inhibiting the complement pathway, such as an anti-C5 antibody capable of inhibiting the complement pathway. In one aspect, the antibody can comprise a monoclonal antibody that inhibits the complement pathway. In other aspects, the drug may comprise a human monoclonal antibody or a humanized monoclonal antibody capable of inhibiting the complement pathway, such as a human monoclonal or humanized monoclonal anti-C5 antibody capable of inhibiting the complement pathway.

In certain embodiments, the complement inhibitor can be an antibody that is capable of inhibiting complement, such as an antibody that blocks the formation of a membrane attack complex (MAC). For example, an antibody complement inhibitor can include an antibody that binds to C5. The anti-C5 antibodies can interact directly with C5 and/or C5b to inhibit the formation and/or physiological function of C5b.

Suitable anti-C5 antibodies are known to those skilled in the art. Antibodies that are exemplified by the individual components of the activated complement, such as antibodies to C7, C9, etc. (see, for example, U.S. Patent No. 6,534,058; U.S. Patent Application No. US 20030129187; and U.S. Patent No. 5,660,825). WO2010015608 and WO199529697 teach to bind to C5 and inhibit antibodies cleaved to C5a and C5b, thus reducing not only C5a but also the formation of downstream complement components.

In certain embodiments, the targeting antibody is a fully human Fc-silent ^TM IgG1 / λ of C5 monoclonal antibodies, such as monoclonal antibody Tesiduolu. SEQ ID No: 1-10 of Table 1 depicts the heavy and light chain CDRs, heavy and light chain variable domains and intact heavy and light chain sequences of the tersomalumab. In an alternative embodiment, the antibody may be a humanized monoclonal antibody, such as may be obtained from Alexion Pharmaceuticals and eculizumab Soliris ^® sold under the trade name of. SEQ ID No: 11-20 of Table 1 depicts the heavy and light chain CDRs, heavy and light chain variable domains and intact heavy and light chain sequences of eculizumab. In an alternate embodiment, the antibody fragment is peculizumab, which is a Fab fragment of eculizumab. In an alternate embodiment, the antibody may be selected from the optimized variants of the 305 antibody as described in Tables 7 and 8 of WO2016098356A1 (as defined herein as "305 variant antibody"; SEQ ID No: of Table 1: 21-84 depicts the heavy and light chain CDRs and the heavy and light chain variable domain sequences of the 305 variant antibody.

In certain embodiments, an antibody that binds C5 or a reactive antibody fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises one or more having a selected from the group consisting of SEQ ID NO: a CDR region of the amino acid sequence of the group consisting of SEQ ID NO: 2 or SEQ ID NO: 3, and wherein the light chain variable region comprises one or more having a selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5 or the CDR regions of the amino acid sequence of the group consisting of SEQ ID NO: 6. In certain embodiments, an antibody that binds to C5 or a reactive antibody fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is comprised of SEQ ID NO: 7 and the light chain is variable The region consists of SEQ ID NO:8. In certain embodiments, the pharmaceutical composition comprises a testoruzumab. In certain embodiments, the pharmaceutical composition comprises eculizumab. In certain embodiments, the pharmaceutical composition comprises pexelizumab. In certain embodiments, an antibody that binds C5 or a reactive antibody fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain consists of SEQ ID NO:9 and the light chain consists of SEQ ID NO:10.

In another embodiment of the present invention, the anti-C5 antibody is eculizumab (Eculizumab homologous antibody), Tesdoruzumab (Tesdoruzumab homologous antibody) or 305 A homologous antibody to a variant antibody, such as an isolated recombinant homologous antibody.

According to the present invention, there is also provided a functional protein comprising an antigen binding portion thereof which specifically binds to a C5 protein and which cross-competes with eculizumab, a teslutuzumab or a 305 variant antibody. In some embodiments, the invention provides an isolated anti-C5 antibody that binds to the same epitope of a C5 protein as compared to an eculizumab, a teslutuzumab or a 305 variant antibody Or an antigen binding fragment thereof. In some embodiments, an antibody of the invention is an isolated monoclonal antibody that specifically binds to a C5 protein. In some embodiments, an antibody of the invention is an isolated human or humanized monoclonal antibody that specifically binds to a C5 protein. In some embodiments, an antibody of the invention is an isolated chimeric antibody that specifically binds to a C5 protein. In some embodiments, the anti-C5 antibodies are single chain antibodies, such as Fab fragments, such as scFv.

A homologous antibody retains the desired functional properties of binding to C5 and inhibiting the cleavage of C5 into C5a and C5b, and in particular the homologous antibody retains the binding of the corresponding estozazumab, eculizumab or 305 variant antibody. effect.

Thus, according to the present invention, the anti-C5 antibody may have a full-length heavy chain and a light chain amine homologous to the amino acid sequence of the estoluzumab or ezukubumab or 305 variant antibody as described herein. A base acid sequence, a variable region heavy chain and a light chain amino acid sequence or a heavy chain and light chain CDR amino acid sequence.

In some embodiments, the homologous antibody comprises a portion of the heavy and light chain amino acid sequences that are 100% identical to the corresponding Tesduzumab, Eculizumab or 305 variant antibody sequences, in particular heavy The chain and light chain CDR amino acid sequences, and other amino acid sequences that are about 80% to 99% identical to the corresponding Tesduzumab, Eculizumab or 305 variant antibody sequences.

In one embodiment, the invention provides an isolated recombinant antibody (or a functional protein comprising an antigen binding portion thereof) comprising a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises SEQ ID NO An amino acid sequence of at least 80%, 90%, 95%, 96%, 97%, 98% or 99% of the amino acid sequence of 7; the light chain variable region comprising an amine of SEQ ID NO: The amino acid sequence is at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence as defined herein above.

In another example, the invention provides for the isolation and recombination comprising a full length heavy chain and a full length light chain An antibody, (or a functional protein comprising an antigen binding portion thereof), wherein: the full length heavy chain comprises at least 80%, 90%, 95%, 96%, 97%, 98% of the amino acid sequence of SEQ ID NO: Or a 99% consensus amino acid sequence; the full length light chain comprising an amine that is at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: Base acid sequence.

As used herein, where the number of gaps to be introduced and the length of each gap are to be considered in order to achieve an optimal alignment of the two sequences, the percent identity between the two sequences is the consensus common to the sequences. A function of the number of positions (ie, consistency % = number of consistent positions / total number of positions x 100). Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described below.

The percent identity between the two amino acid sequences can be calculated using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:1 1-17, 1988) (which has been incorporated into the ALIGN program (version) 2.0)), determined using a PAM120 weight residue table, a gap length penalty of 12, and a void penalty of 4. In addition, the percent identity between the two amino acid sequences can be performed using the Needleman and Wunsch (J. Mol. Biol. 48: 444-453, 1970) algorithm (which has been incorporated into the GCG suite software (available at http:/). /www.gcg.com obtained in the GAP program), using the Blossom 62 matrix or PAM250 matrix, and the gap weights 16, 14, 12, 10, 8, 6 or 4 and the length weights 1, 2, 3, 4, 5 or 6 to determine.

Moreover, in another embodiment, modifications can be made to improve one or more binding properties (eg, affinity) of an antibody of interest, referred to as "affinity maturation." Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce mutations and the effects on antibody binding or other functional properties of interest can be assessed in in vitro or in vivo assays. Conservative modifications can be introduced and the mutation can be an amino acid substitution, addition or deletion. Furthermore, typically no more than one, two, three, four or five residues are altered within the CDR regions. According to the present invention, the present invention provides an isolated anti-C5 monoclonal antibody or a function thereof. A sex antigen binding portion consisting of a heavy chain variable region having: a VH CDR1 region having the amino acid sequence of SEQ ID NO: 1 or having a SEQ ID NO: 1 compared to SEQ ID NO: An amino acid sequence substituted, deleted or added to one, two, three or four amino acids; a VH CDR2 region having the amino acid sequence of SEQ ID NO: 2 or having one compared to SEQ ID NO: Amino acid sequence substituted, deleted or added with two, three, four or five amino acids; a VH CDR3 region having the amino acid sequence of SEQ ID NO: 3 or having one compared to SEQ ID NO: Amino acid sequence substituted, deleted or added with two, three, four or five amino acids; a VL CDR1 region having the amino acid sequence of SEQ ID NO: 4 or having one compared to SEQ ID NO: Amino acid sequence substituted, deleted or added with two, three, four or five amino acids; a VL CDR2 region having the amino acid sequence of SEQ ID NO: 5 or having one compared to SEQ ID NO: Amino acid sequence substituted, deleted or added with two, three, four or five amino acids; and a VL CDR3 region having the amino acid sequence of SEQ ID NO: 6 or compared to SEQ ID N O:6 has an amino acid sequence substituted, deleted or added with one, two, three, four or five amino acids.

In other aspects, the complement inhibitor is a rehabilitative. The recombinant agent in the development of Akari Therapeutics is a recombinant small protein derived from the saliva of Ornithodoros moubata . Rehabilitation binds to complement factor C5 and inhibits the activation of C5, the release of C5a, and the formation of a membrane attack complex.

method

A method for treating a transplant-associated microangiopathy after transplantation (for example, a solid transplantation or a cell transplantation) for an individual in need thereof, such as TAM after stem cell transplantation (TAM-SCT), such as TAM after precursor cell transplantation (TAM-) PCT), for example, TAM (TAM-HPCT) after hematopoietic precursor cell transplantation, such as TAM after post-hematopoietic stem cell transplantation (TAM-HSCT), such as TAM after autologous or allogeneic hematopoietic stem cell transplantation.

The method can comprise the step of administering a drug, such as a psychotherapin, or an antibody capable of inhibiting terminal complement, such as an anti-C5 antibody. The terminal complement may comprise a monoclonal antibody capable of inhibiting terminal complement or, in another embodiment, a human or human monoclonal antibody capable of inhibiting terminal complement. In one embodiment, the antibody can be a Tesdoruzumab or a homologous antibody as defined herein above. In another embodiment, the antibody can be eculizumab or a homologous antibody thereof as defined herein above. In another embodiment, the antibody can be a 305 variant antibody ("305 variant antibody") as described in Tables 7 and 8 of WO2016098356A1.

individual

In some embodiments, the individual is a human, such as a patient. The patient can be an adult of any weight or any patient having a body weight greater than or equal to 40 kg. Alternatively, the patient may have a body weight of less than 40 kg but greater than or equal to 30 kg, a body weight of less than 30 kg but greater than or equal to 20 kg, and a body weight of less than 20 kg but greater than or equal to 10 kg.

In some embodiments, the individual is Two years old child. In an alternate embodiment, the individual is a child greater than 2 years old but less than 12 years old. In an alternate embodiment, the individual is greater than or equal to 12 years old. In an alternate embodiment, the individual is an adult greater than or equal to 16, such as 18 years old.

Suitable methods for identifying an individual as having an individual with TAM-PCT or TAM-HSCT, suspected of having TAM-PCT or TAM-HSCT, or at risk of developing TAM-PCT or TAM-HSCT are known in the medical arts. Symptoms include systemic vascular injury, kidney damage, serositis, pulmonary hypertension, and multiple systemic organ failure. Thus, a variety of tests can be performed on an individual to determine if the individual has: - an increase in lactate dehydrogenase (an increase above any normal range); - thrombocytopenia, platelet count <50×10e9/L or platelet count decreased by more than >50% compared to the highest value achieved after transplantation; - anemia below the normal lower limit or anemia supported by transfusion according to central criteria; - Hemolytic cells on the peripheral blood smear (2 per HPF) or histological signs of microvascular disease; and/or - no coagulopathy at screening (no uncompensated disseminated intravascular coagulation, DIC).

Before treatment, the individual may receive Neisseria meningitidis (N.meningitides) vaccine. Such vaccines should take into account the prevalent serotypes in the geographic area of the individual being treated. In addition, individuals less than 18 years old can be vaccinated in order to prevent Streptococcus pneumoniae (S.pneumoniae) and Haemophilus influenzae type b (H.influenzae).

Dosing plan

Previous studies have used a regimen that follows the typical dosing schedule for aHUS when patients are diagnosed with thrombotic microangiopathy after HSCT (weekly infusion of 900 mg of eculizumab for 4 weeks, followed by every 14 days) A maintenance dose of 1200 mg) (Legendre CM et al. (2013) N. Engl. J. Med, 368: 21169). However, in some studies, a lower initial dose is used based on the patient's weight and then the dose is increased. For example, Okano M et al. ((2014) Bone Marrow Transplantation, 49: 1116-8) administered eculizumab to patients with TA-TMA based on the dose used for aHUS (based on patient weight -23 kg) 600mg per week as the initial dose). This dose was then increased to 900 mg per week for the next 3 doses. The dose of the sixth eculizumab was reduced to 600 mg, and then the eculizumab was administered every two weeks at the 7th to 14th (last time) administration.

Jodele S et al. (2014) Biol. Blood Marrow Transplant, 20: 518-525 describes the course of administration, in which the minimum level of eculizumab and its efficacy are considered The entire dose. Patients weighing <40 kg started with an intravenous dose of 600 mg. Patients weighing >40 kg started with 900 mg intravenously as the first dose. Subsequent dose adjustments are as follows:

- If the minimum level is reported to be therapeutic before the next weekly dose, the same induction dose will continue for each week.

- If the patient reaches the next weekly dose phase and the lowest concentration of eculizumab is less than therapeutic, increase the dose by 300 mg/dose.

- If a lower than therapeutic result is reported 4 to 5 days after the previous dose, an additional induction dose is given when the results are obtained.

- If the results for dose adjustment are not available, the same eculizumab induction dose is continued for each week until the minimum concentration of the eculizumab is recorded above the therapeutic amount.

TMA laboratory indicators are recorded daily during inpatient stays and are recorded at least twice a week in outpatient settings. The weekly induction therapy was continued until the patient reached a hematologic TMA response and the eculizumab content was >99 μg/mL, at which time the maintenance time course was initiated. Guidelines for stopping eculizumab include normalization of hematology TMA parameters and improvement of renal function.

According to the present invention, there is provided an improved administration regimen for the treatment or prevention of TAM, in particular TAM after solid transplantation (or as a complication thereof) or TAM after cell transplantation (or as a complication thereof), such as TAM after stem cell transplantation (TAM-SCT), for example, TAM (TAM-PCT) after precursor cell transplantation, such as TAM (TAM-HPCT) after hematopoietic precursor cell transplantation, such as TAM (TAM-HSCT) after hematopoietic stem cell transplantation, wherein the therapy involves administration of C5 An inhibitor (eg, an anti-C5 antibody, eg, eculizumab, tessudouzumab, 305 variant antibody, or a homologous antibody thereof) as defined herein above, for example, comprising a administration of testoruzumab .

In one aspect, the administration of a drug (eg, an antibody, eg, an anti-C5 antibody as defined herein) can be administered daily, or every two days, or every three days, every four days, every five days, every six days, Every 7 days, every 8 It is repeated every day, every 9 days, every 10 days. In certain aspects, the drug, for example, an anti-C5 antibody as defined herein, is administered weekly.

In another embodiment, the drug (eg, an antibody, eg, an anti-C5 antibody as defined herein) is administered weekly between 1 to 5 weeks, eg, 2 weeks, eg, 3 weeks, eg, 4 weeks, followed by each 2 weeks or every 3 weeks.

The medicament (eg, an antibody, eg, an anti-C5 antibody as defined herein) can be used for at least one administration, or at least two administrations, or at least three administrations, or at least four administrations, or at least five administrations, Or at least six administrations, or at least seven administrations, or at least eight administrations, or at least nine administrations, or at least 10 administrations, or at least 11 administrations, or at least 12 administrations, or At least 13 administrations, or at least 14 administrations, or at least 15 administrations, or at least 16 administrations, or at least 17 administrations, or at least 18 administrations, or at least 19 administrations, or at least 20 doses, or even more doses in certain aspects. In one aspect, this usage can be performed until a hematologic response or a complete disease response is achieved in the individual.

In certain aspects, the drug (eg, an antibody, eg, an anti-C5 antibody, for example, selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody, and homologous antibodies thereof as defined herein above. Administration of the anti-C5 antibody of the group can be carried out over a period of from about three weeks to about 30 weeks or from about four weeks to about 30 weeks or longer, for example about 4 weeks, about 5 weeks, about 6 weeks. About 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks. During the treatment period, for example between 1 and 30 weeks, for example between 1 and 20 weeks, for example between 1 and 17 weeks, for example between 1 and 15 weeks, for example between 1 and 12 weeks, the drug ( For example, an antibody, such as an anti-C5 antibody as defined herein, such as Tesdoruzumab, can be administered weekly.

In other aspects, the drug (eg, an antibody, eg, an anti-C5 antibody, eg, eculizumab, Tesdoruzumab, 305 variant antibody, or a homologous antibody thereof) as defined herein above, is administered It can be carried out in a period of up to 50 weeks, for example up to 45 weeks, for example up to 40 weeks, for example up to 35 weeks, for example up to 30 weeks.

In another aspect, the medicament (eg, an antibody, eg, an anti-C5 antibody, eg, eculizumab, Tesdoruzumab, 305 variant antibody, or a homologous antibody thereof) as defined herein above) The administration can be carried out in one month, two months, three months, four months, five months, six months or longer, for example, one year or longer. The drug (eg, an antibody, eg, an anti-C5 antibody as defined herein, eg, Tesduzumab) can be administered weekly during the treatment period.

In another aspect, the medicament (eg, an antibody, eg, an anti-C5 antibody, eg, eculizumab, Tesdoruzumab, 305 variant antibody, or a homologous antibody thereof, as defined herein above) Administration can be between 1 and 6 months, such as 1 to 5 months, such as 1 to 4 months, such as 1 and 3 months, such as 2 to 6 months, such as 2 to 5 months, such as 2 to 4 months, for example 2 to 3 months, for example 3 to 6 months, for example 3 to 5 months, for example 3 to 4 months, for example 4 to 6 months, for example 4 to 5 months, for example 5 to 6 Conducted during the period between months. The drug (eg, an antibody, eg, an anti-C5 antibody as defined herein, eg, Tesduzumab) can be administered weekly during the treatment period.

In some aspects, the C5 inhibitor (eg, an anti-C5 antibody, eg, eculizumab, Tesdoruzumab, 305 variant antibody, or a homologous antibody thereof) as defined herein above, Different dose administrations are first administered at an induction dose during a first time period (also referred to as an induction phase) and then administered at a second, different dose during the maintenance period. The induction phase plus the total duration of the maintenance period can be as defined above.

The induction phase is for example a C5 inhibitor (which is selected from the group consisting of AI selected as defined herein above) Anti-C5 antibodies, such as eculizumab, Tesduzumab or 305 variant antibodies, of the group of monoclonal antibodies, Tesduzumab, 305 variant antibodies and their homologous antibodies can last 1 to 8 weeks, for example 1 to 6 weeks, for example 1 to 4 weeks, for example 1 week, for example 2 weeks, for example 3 weeks, for example 4 weeks, for example 5 weeks, for example 6 weeks, for example 7 weeks, for example 8 weeks.

The maintenance period is, for example, a C5 inhibitor (which is an anti-C5 antibody selected from the group selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its cognate antibody as defined herein above, eg Eculizumab, Tesdoruzumab or 305 variant antibody) can last from 1 to 11 months, for example from 1 to 8 months, for example from 1 to 6 months, for example from 1 to 4 months, for example 2 to 6 months, for example 2 to 5 months, for example 2 to 4 months, for example 3 to 6 months, for example 3 to 4 months, for example 3 months, for example 4 months, for example 5 months, for example 6 month.

The induced dose can be about 2000 mg, 1700 mg, such as about 1500 mg, such as about 1400 mg, such as about 1300 mg, such as about 1200 mg, such as about 1100 mg, such as about 1000 mg, such as about 900 mg, such as about 800 mg, of the anti-C5 antibody, for example as herein Tesduzumab, eculizumab, 305 variant antibody or homologous antibody as defined above. For example, for an individual weighing 40 kg or greater, about 900 mg, such as about 800 mg, such as about 700 mg, for example about 600 mg, of Tesduzumab, Eculizumab, 305 variant antibody or as defined herein above or a homologous antibody thereof, for an individual weighing from about 30 kg to about 40 kg, about 600 mg of Tesduzumab, Eculizumab, 305 variant antibody or a homologous antibody thereof as defined herein above, An individual weighing from about 20 kg to about 30 kg, about 600 mg of Tesduzumab, Eculizumab, 305 variant antibody or a homologous antibody as defined herein above, for weighing from about 10 kg to about 20 kg Individual, about 300 mg of Tesduzumab, Eculizumab, 305 variant antibody or homologous antibody as defined herein above, for individuals weighing from about 5 kg to about 10 kg.

The C5 inhibitor (eg, an anti-C5 antibody, eg, selected from the group consisting of an anti-C5 antibody selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its cognate antibody as defined herein above, eg, Ai The inducing dose of the library of monoclonal antibody, the estoluumab or the 305 variant antibody may be comprised between about 10 mg/kg and 40 mg/kg, for example from about 10 mg/kg to 35 mg/kg, for example from about 10 mg/kg to 30 mg/ Kg, for example, in the range of about 10 mg/kg to 25 mg/kg, such as from about 10 mg/kg to 20 mg/kg, for example about 40 mg/kg, such as about 35 mg/kg, such as about 30 mg/kg, such as about 25 mg/kg, For example about 20 mg/kg, such as about 15 mg/kg, such as about 10 mg/kg. In one aspect, the induced dose is, for example, a C5 inhibitor that is selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its cognate antibody, as defined herein above. Anti-C5 antibodies, such as eculizumab, testoluumab or 305 variant antibody, are about 15 mg/kg. In another aspect, the inducing dose is, for example, a C5 inhibitor (which is selected from the group consisting of eculizumab, Tesdoruzumab or 305 variant antibodies and homologous antibodies thereof as defined herein above) The anti-C5 antibody, such as eculizumab, Tesdoruzumab or 305 variant antibody, is about 20 mg/kg. In another aspect, the induced dose is, for example, an anti-C5 antibody (selected from the group selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its homologous antibody as defined herein above, eg The condition of eculizumab, Tesdoruzumab or 305 variant antibody is about 25 mg/kg.

A maintenance dose of a medicament of the invention may be about 1500 mg, about 1200 mg, about 1000 mg, about 800 mg, about 700 mg, about 500 mg, about 400 mg, about 300 mg of, for example, an anti-C5 antibody, such as a testoru single as defined herein above. Anti-, eculizumab, 305 variant antibody or its homologous antibody. For example, the maintenance dose is, for example, an anti-C5 antibody (selected from a group selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its homologous antibody as defined herein above, eg, the Aiku group Status of monoclonal antibody, Tesdoruzumab or 305 variant antibody) The lower may comprise from about 300 mg to about 1500 mg, such as from about 300 mg to about 1200 mg, such as from about 300 mg to about 1000 mg, such as from about 300 mg to about 800 mg, such as from about 400 mg to about 1500 mg, such as from about 400 mg to about 1200 mg, such as from about 400 mg to about 1000 mg, for example from about 400 mg to about 800 mg, such as from about 500 mg to about 1500 mg, such as from about 500 mg to about 1200 mg, such as from about 500 mg to about 1000 mg, such as from about 500 mg to about 800 mg.

For example, for an individual weighing 40 kg or greater, about 600 mg, such as about 400 mg, about 300 mg of an anti-C5 antibody (selected from eculizumab, Tesdoruzumab, as defined above, as defined herein above, A population of 305 variant antibodies and their cognate antibodies, such as eculizumab, Tesdoruzumab or 305 variant antibodies).

The maintenance dose is, for example, an anti-C5 antibody (selected from a group selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its homologous antibody as defined herein above, eg, eculizumab, special The condition of the stiluzumab or 305 variant antibody may be included in the range of from about 5 mg/kg to 25 mg/kg, for example from about 5 mg/kg to 20 mg/kg, for example from about 5 mg/kg to 10 mg/kg, for example It is about 30 mg/kg, such as about 25 mg/kg, such as about 20 mg/kg, such as about 15 mg/kg, such as about 10 mg/kg, such as about 5 mg/kg.

In one aspect, the maintenance dose is, for example, an anti-C5 antibody (selected from a group selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its homologous antibody as defined herein above, eg, Ai The condition of the library monoclonal antibody, the testoluumab or the 305 variant antibody is about 5 mg/kg.

In another aspect, the induced dose is about 10 mg/kg. In another aspect, the induced dose is, for example, an anti-C5 antibody (selected from the group selected from the group consisting of eculizumab, Tesdoruzumab, 305 variant antibody and its homologous antibody as defined herein above, eg Ekuleimumab, Testo The condition of ruumab or 305 variant antibody is about 15 mg/kg.

In certain aspects (wherein the drug is an anti-C5 antibody, such as eculizumab, Tesdoruzumab, 305 variant antibody or homologous antibody as defined herein above), can be administered The step is until a serum level of more than or at least about 99 [mu]g/mL, or at least or more than about 100 [mu]g/mL, or at least or more than about 200 [mu]g/ml, or at least or at least about 300 [mu]g/ml is reached. The administration step can be repeated daily, or every two days, or every three days, or every four days, or every five days, or every six days, or every seven days, until an excess of at least about 99 μg/mL is achieved in the individual. Or at least or more than about 100 μg/mL, or at least or more than about 150 μg/ml, or at least or more than about 200 μg/ml, or at least or more than about 300 μg/ml. The administration step can be repeated daily, or every two days, or every three days until an over or at least about 99 μg/mL, or at least or more than about 100 μg/mL, or at least or more than about 200 μg/ml, or at least, is achieved in the individual. Or a serum content of more than about 300 μg/ml. One of ordinary skill will readily appreciate the determination of the dosage in a patient based on the patient's weight.

A C5 inhibitor (specifically an anti-C5 antibody, for example selected from the group consisting of eculizumab, testoluzumab or 305 variant antibody as defined herein above), may be present in the individual in an amount sufficient to achieve a therapeutic level. The administration step is carried out in the form of a group of source antibodies, such as eculizumab, testoluumab or 305 variant antibody. The administration step can comprise at least one dose, or at least two doses, or at least three doses, or at least four doses, or, in some aspects, more than four doses.

According to the invention, the C5 inhibitor (eg, an anti-C5 antibody, eg, eculizumab, testoluumab, 305 variant antibody or homologous antibody thereof) as defined herein may further comprise measuring total complement Activity (CH50) to obtain a CH50 measurement, wherein the individual is administered a C5 inhibitor until the CH50 value obtained from the patient is about 0 to 3 CAE units (as measured by enzyme immunoassay) , or where the CH50 measurement is 0 to 15 CH50 units (eg, using hemolytic The method utilizes standardized sheep red blood cell measurements).

In certain aspects, methods for treating or preventing TAM (eg, TAM-PCT, eg, TAM-SCT, eg, TAM-HPCT, eg, TAM-HSCT) are provided, comprising administering a C5 inhibitor (eg, an anti-C5 antibody) For example, the steps of eculizumab, testoluumab, 305 variant antibody or homologous antibody thereof as described above.

In another embodiment, a method for treating or preventing TAM (eg, TAM-PCT, eg, TAM-SCT, eg, TAM-HPCT, eg, TAM-HSCT) is provided, comprising the steps of: a) using a complement inhibitor (eg, an anti-C5 antibody, eg, eculizumab, testoluumab, 305 variant antibody, or a homologous antibody thereof as defined herein above) is measured for total complement activity (CH50) prior to treatment, thereby obtaining An initial CH50 measurement; b) administration of the complement inhibitor as defined in a); and c) measuring total CH50 activity after administration of the complement inhibitor, obtaining a post-treatment CH50 measurement, wherein The CH50 measurement with the complement inhibitor up to the treatment is about 0 to 3 CAE units (as measured by enzyme immunoassay), or wherein the CH50 measurement is 0 to 15 CH50 units (eg, using hemolysis) The sexual method uses standardized sheep red blood cell measurements).

The administering step can comprise administering an anti-C5 antibody, such as, for example, Tesduzumab, Eculizumab, 305 variant antibody or a homologous antibody as defined herein above, and the administering step can be sufficient to subside During the time period of HSCT-TMA. In some aspects, the administering step is performed during a time period as defined herein above, for example about three to thirty weeks, such as four to about 15 weeks, such as four to about 17 weeks, or up to 20 weeks, or up to 25 weeks. Or until the dose of the anti-C5 antibody (eg, Tesdoruzumab, Eculizumab, 305 variant antibody or homologous antibody as defined herein above) is sufficient to reduce the CH50 content to 0 Up to 3 CAE units (if utilized Enzyme immunoassay), or where the CH50 is measured from 0 to 15 CH50 units (eg, using standardized hemoglobin measurements using a hemolysis method).

The administering step can comprise administering an anti-C5 antibody, such as, for example, Tesduzumab, Eculizumab, 305 variant antibody or a homologous antibody as defined herein above, and the administering step can be as herein The time defined above is, for example, sufficient to achieve a favorable hematologic response, wherein the favorable hematologic response comprises a regression of the hematology HSCT-TMA indicator; or sufficient to substantially inhibit the CH50 content. Such indicators may include, but are not limited to, the normalization of LDH, the release of red blood cell and platelet transfusion requirements, and the disappearance of lytic blood cells or any other such criteria as would be readily understood by one of ordinary skill. For example, the administration can be continued until the split blood cell reaches <2/microscopic high power field (HPF).

The administration step can be carried out for a period of time sufficient to achieve a complete response, wherein the complete response comprises normalization of the individual's hematological parameters and renal response, including but not limited to cystatin C assessment of glomerular filtration rate (eGFR) doubling and proteinuria achieve improvements below the range of nephropathy (as defined by the use of a urinary protein to creatinine ratio of less than 2 mg/mg), or other criteria as would be readily understood by one of ordinary skill.

In certain aspects, the drug can be administered to an individual during the time period as defined above (eg, an anti-C5 antibody, such as, for example, Tesduzumab, Ecco, as defined herein above) An anti-, 305 variant antibody or a homologous antibody thereof, for example, multiple times a day, daily, weekly, or monthly. If the initial or subsequent dose does not subside HSCT-TMA or is insufficient to achieve a favorable hematologic response as defined herein above, or insufficient to adequately inhibit CH50 content, it may be administered on a daily, weekly, or monthly basis. dose. In such cases, the additional dose can be a greater dose than the initial or most recently administered dose. In certain aspects, the dosage can be increased by about 100 mg, or about 200 mg, or about 300 mg, or about 400 mg, or about 500 mg.

As used herein, "sufficiently inhibiting CH50 content" means 0 to 3 CAE units (as measured by enzyme immunoassay), or 0 to 15 CH50 units (eg, using standardized hemoglobin measurements using a hemolysis method), As described herein.

In one aspect, a method of determining the relative amount of a complement inhibitor in an individual administered with a complement inhibitor is disclosed. In this aspect, the method can comprise the step of measuring total complement activity (CH50) in a sample obtained from the individual. The total complement inhibitor may comprise, for example, a Tesduzumab, an eculizumab or a 305 variant antibody.

In one aspect, a method of optimizing an anti-C5 antibody (eg, a Tesduzumab, an eculizumab, a 305 variant antibody, or a homologous antibody thereof as defined herein above) is disclosed, The time course of administration in individuals with or without any syndrome of TMA after HSCT. In this aspect, the method can comprise the steps of: a) determining total complement activity (CH50) in the individual treated with the induction dose of the anti-C5 antibody; b1) administering if the CH50 content is not sufficiently inhibited The second induced dose; or b2) if the CH50 content is sufficiently inhibited, the weekly induced dose is administered; c) if the CH50 content is not sufficiently inhibited after the second induced dose, the administration is increased by about 100 mg to about 400 mg, For example, an induction dose of about 300 mg; wherein the individual is administered an anti-C5 antibody, such as, for example, Tesduzumab, Eculizumab, 305 variant antibody or a homologous antibody as defined herein above, up to TAM The hematological symptoms resolve, such as the regression of the hematology HSCT-TAM indicator; or sufficient to adequately inhibit the CH50 content, as defined above.

The method can further comprise the step of providing a maintenance dose to maintain CH50 inhibition.

The drug, eg, an antibody, eg, an anti-C5 antibody as defined herein, may be via such an item Any method known in the art is administered, such as intravenously, subcutaneously, intramuscularly, and/or orally.

Instance

To determine the effect of anti-C5 antibody Tesduzumab in patients with TAM-HSCT, randomized, standard care (SoC) controls, open markers, multicenter studies were designed. The study population was for patients with TAM after transplantation of hematopoietic progenitor cells from related or unrelated donors for malignant and non-malignant diseases after myeloablative or nonmyeloablative modulation.

The study consisted of: a screening period of up to 28 days; a treatment period of 16 weeks, which can be extended to a maximum of 45 weeks (without adequate inhibition of serum complement after 16 weeks); 36 weeks follow-up And at the end of the 52-week study visit (EOS) (Figure 1). The duration of follow-up depends on the duration of treatment. Patients who have been treated for more than 41 weeks are treated directly with EOS.

Nearly 40 patients were randomized to receive standard care (SoC) (including but not limited to immunosuppressive drugs such as rituximab, and plasmapheresis) or Tesduzumab plus SoC (not These include plasmapheresis and inhibition therapy, such as eculizumab, high-dose IVIG, plasmapheresis in the Tesdoruzumab-treated group, or live vaccination in the Tesdoruzumab-treated group). Patients were included in the study if they had a diagnosis of TAM and a poor prognostic indicator. Only allowed to 5 The 12-year-old patient was administered with Tesdoruzumab and the treatment was analyzed in the late 4 weeks and revealed no safety issues. A 2-year-old child was included.

Patients randomized to Tesduzumab received 20 mg/kg body weight on Days 1, 8 and 15 of the study, followed by a weekly dose of 10 for a total of 16 weeks of remaining treatment duration Mg/kg. In the case where the serum complement activity was not sufficiently inhibited after the 10 mg/kg dose (CH50 analysis was lower than LLoQ), it was possible to change back to the weekly injection of 20 mg/kg until the end of the treatment.

Patients who presented with worsening disease (defined below) after two weeks of treatment (Day 15) or later were considered to have failed and were exchanged for alternative treatment (SoC or Tesdorumab).

‧ Increased hemocyte count (+50% or more compared to baseline), ‧ and/or increased erythrocyte or platelet transfusion requirements (+50% or more two weeks before the start of treatment), ‧ and / or increased proteinuria (+50% or more compared to baseline)

Patients who showed no response (defined below) at 4 weeks (Day 29) or later until 16 weeks of treatment were considered treatment failures and were exchangeable to other treatment groups. Exchange therapy can be performed as soon as the data is available.

‧The ruptured blood cell count is not reduced (less than 25% improvement from baseline)

‧Continuous red blood cell or platelet transfusion requirements (less than 25% improvement in required number two weeks before treatment)

‧ and / or do not respond to proteinuria (less than 25% reduction in proteinuria compared to baseline)

Patients can only be exchanged once in the study treatment group.

If the data is not available on the 15th or 29th day or at the subsequent scheduled visit and the improvement is suspected to be inadequate, an irregular visit is allowed to check the above parameters. Patients who have switched from SoC to Tesduzumab need to repeat the visit and dosing schedule from the visit 3 at the first dose of the study drug. Patients who changed from Tesdoruzumab to SoC continued their visit according to the assessment schedule.

Patients with inadequate inhibition of serum complement activity (based on CH50 analysis) who continue to be treated with Tesdoruzumab for a maximum of 45 weeks if considered safe by the investigator. The sponsor discussed and agreed on a case-by-case basis on the decision to continue the dose after 16 weeks.

All patients received antibiotics effective against the prophylactic dose of N. meningitidis during the entire treatment period and after the last 4 weeks of treatment. The choice of antibiotic drugs is in accordance with hospital standards.

The primary endpoint was assessed at week 17 (i.e., 1 week after the last dose at week 16).

<110> Swiss Business Novartis

<120> Use of C5 inhibitors in transplantation-related microangiopathy

<130> PAT057104

<150> US62/240150

<151> 2015-10-12

<160> 84

<170> PatentIn version 3.5

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<213> Artificial sequence

<220>

<223> 305L020 CDRL3

<400> 66

<210> 67

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> 305L020 VH

<400> 67

<210> 68

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> 305L020 VL

<400> 68

<210> 69

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 CDRH1

<400> 69

<210> 70

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 CDRH2

<400> 70

<210> 71

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 CDRH3

<400> 71

<210> 72

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 CDRL1

<400> 72

<210> 73

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 CDRL2

<400> 73

<210> 74

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 CDRL3

<400> 74

<210> 75

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 VH

<400> 75

<210> 76

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> 305L022 VL

<400> 76

<210> 77

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 CDRH1

<400> 77

<210> 78

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 CDRH2

<400> 78

<210> 79

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 CDRH3

<400> 79

<210> 80

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 CDRL1

<400> 80

<210> 81

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 CDRL2

<400> 81

<210> 82

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 CDRL3

<400> 82

<210> 83

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 VH

<400> 83

<210> 84

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<223> 305L023 VL

<400> 84

Claims (23)

Use of a C5 inhibitor, such as an anti-C5 antibody, for the manufacture of a medicament for the prevention or treatment of a transplant-associated microangiopathy (TAM) in a patient in need thereof, such as TAM after cell transplantation. The use of a C5 inhibitor according to claim 1, wherein the C5 inhibitor is administered to a patient in need thereof at a dose of about 50 mg/kg, for example 20 mg/kg. The use of the C5 inhibitor of claim 1, wherein the C5 inhibitor is administered to a patient in need thereof at a dose of from about 800 mg to about 2000 mg, for example from about 1000 mg to about 2000 mg. The use of the C5 inhibitor of claim 1, wherein the C5 inhibitor is administered to a patient in need thereof at a dose of about 30 mg/kg, for example 10 mg/kg. The use of a C5 inhibitor according to claim 1, wherein the C5 inhibitor is administered to a patient in need thereof at a dose of from about 400 mg to about 1000 mg, for example from about 500 mg to about 1000 mg. The use of a C5 inhibitor according to any one of claims 1 to 5, wherein the C5 inhibitor is administered to a patient in need thereof during a period of between 1 week and 8 weeks, for example 3 weeks or 4 weeks . The use of a C5 inhibitor according to any one of claims 1 to 5, wherein the C5 inhibitor is administered during a period of between 1 month and 11 months, for example 4 months or 5 months There are patients in need. The use of the C5 inhibitor of claim 1, wherein the C5 inhibitor first doses the patient in need thereof at an induction dose during the induction phase, and then administers the patient in need at a maintenance dose during the maintenance period, wherein The maintenance dose is lower than the induction dose. The use of the inhibitor of claim 8, wherein the inducing dose is as defined in claim 2 or 3. The use of a C5 inhibitor according to claim 8 or 9, wherein the induction phase is as defined in claim 6. The use of the C5 inhibitor of claim 9 wherein the maintenance dose is as defined in claim 4. The use of the C5 inhibitor of claim 10, wherein the maintenance dose is as defined in claim 4. The use of the C5 inhibitor of claim 9 wherein the maintenance dose is as defined in claim 5. The use of the C5 inhibitor of claim 10, wherein the maintenance dose is as defined in claim 5. The use of the C5 inhibitor of claim 9 wherein the maintenance period is as defined in claim 7. The use of a C5 inhibitor according to any one of claims 1 to 5, wherein the C5 inhibitor is administered weekly. The use of a C5 inhibitor according to any one of claims 1 to 5, wherein the C5 inhibitor is administered until the hematological symptoms of TMA resolve. The use of a C5 inhibitor according to any one of claims 1 to 5 for preventing or treating TAM (TAM-PCT) after precursor cell transplantation or TAM after hematopoietic stem cell transplantation, for example, in allogeneic hematopoietic stem cells TAM (TAM-HSCT) after transplantation. The use of a C5 inhibitor according to any one of claims 1 to 5 for the prevention or treatment of TAM in a patient who has been transplanted by, for example, HPCT or HSCT. The use of a C5 inhibitor according to any one of claims 1 to 5, wherein the C5 inhibitor is selected from the group consisting of tesidolumab, eculizumab, and a homologous antibody thereof. Groups, such as Tesdorumab. An in vitro method for monitoring the efficacy of a treatment for TAM-PCT or TAM-HSCT, such as allogeneic TAM-HSCT, in an individual who has been transplanted, such as HSCT, the method comprising the steps of: a. Total complement activity (CH50) is measured in the sample of the individual, and b. Tesdorumab is administered to the therapy as defined in any one of claims 2 to 15. An in vitro method for monitoring the efficacy of a treatment for TAM-PCT or TAM-HSCT, such as allogeneic TAM-HSCT, in an individual who has been transplanted, such as HSCT, the method comprising the steps of: a. The total complement activity (CH50) is measured in the sample, and b. a C5 inhibitor, such as an anti-C5 antibody, is administered in a therapy as defined in any one of claims 2 to 15. The method of claim 21 or 22, wherein the C5 inhibitor is selected from the group consisting of Tesduzumab, Eculizumab, and a homologous antibody thereof, such as Tesduzumab.