Compositions and methods for treating Huntington's disease

Abstract

The present disclosure generally relates to a method of treating Huntington's disease in a subject in need thereof, the method comprising determining that the subject has elevated C4a levels or an elevated C4a / C4 ratio, and administering to the subject an inhibitor of the classical complement pathway.

Description

[Technical field]

[0001] Related Applications This patent application claims priority to U.S. Provisional Patent Application No. 63 / 349,305, filed June 6, 2022, and U.S. Provisional Patent Application No. 63 / 295,213, filed December 30, 2021, each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative condition characterized by chorea and dystonia, cognitive decline and psychiatric disability. A specific genetic mutation involves the expansion of a trinucleotide (cytosine, adenine, and guanine [CAG]) repeat in the huntingtin gene (Htt) on chromosome 4p. The unstable CAG repeat is translated into a polyglutamine expansion in the huntingtin protein. Age of onset and disease severity have been found to be associated with the number of CAG repeats in the Htt gene, with those individuals with the earliest onset having the greatest number of repeats. The normal function of the huntingtin protein is unknown, but current understanding supports mutant proteins with expanded polyglutamine sequences as toxic to brain cells.

[0003] In general, HD symptoms progressively worsen and invariably lead to death. HD is often divided into three broad phases. In the early stages, HD patients experience mild symptoms but are largely functional and able to work and live independently. In intermediate stage HD, symptoms including chorea and cognitive decline are more prominent and patients may not be able to work or care for themselves. In late stage HD, patients require assistance with all aspects of daily life and have dementia, akinetic dystonia, and bradycardia that predominates in progressive disease. Death typically occurs within 15-20 years of disease onset and is usually associated with complications of immobility, infections, especially pneumonia, and cardiac disease. The Unified Huntington's Disease Rating Scale (UHDRS), first published in 1996 and revised in 1999 and 2005, is often used to stage patients with HD based on assessing motor function, cognition, behavior, independence, functional ability, and total functional ability.

[0004] Neuropathologically, HD is characterized by neuronal loss primarily in the striatum and cerebral cortex. Certain neuronal populations are more affected, including those in the striatum of the basal ganglia. The mechanism by which polyglutamine aggregation causes neurodegeneration is unclear, but insights into the pathophysiology of HD are emerging from animal models. Early synaptic dysfunction is a key feature, manifested by dysregulation of glutamate release in the striatum, followed by progressive disconnection between the cortex and the striatum. Some of the changes in late HD may be compensatory mechanisms designed to address early synaptic and receptor dysfunction. These findings suggest that HD treatments need to be designed according to the stage of disease progression, although synaptic dysfunction and loss occur early and continue throughout disease progression.

[0005] To date, no treatment has been shown to delay the onset of HD or slow its progression. Treatment focuses on managing specific symptoms. Patient care may include a wide range of physicians to address various physical and psychological symptoms. Chorea is often associated with cognitive and psychological aspects of the disease, such as anxiety and depression. Impairments in one area usually lead to problems in another area. Furthermore, there is an unmet need to identify mediators of neurological dysfunction in HD and characterize the natural history so that treatment effects can be accurately evaluated. Thus, there is a need in the art for new therapies to prevent and treat HD. Summary of the Invention

[0006] The present disclosure generally relates to a method of treating Huntington's disease in a subject in need thereof, the method including determining whether the subject has an elevated C4a level or an elevated C4a / C4 ratio, and administering to the subject an inhibitor of the classical complement pathway if the subject has an elevated C4a level or an elevated C4a / C4 ratio. A therapeutically effective amount of the inhibitor can be administered.

[0007] The elevated C4a level may be higher than the C4a level of a normal or healthy subject, such as a subject of similar age. The elevated C4a level may be higher than a reference C4a level. For example, the reference C4a level is equal to or higher than the median C4a level of samples from subjects with Huntington's disease (such as subjects of the same age). In other embodiments, the reference C4a level is equal to or higher than the 75th percentile of C4a levels in samples from normal or healthy subjects (subjects not suffering from Huntington's disease), such as subjects of similar age.

[0008] In some embodiments, the elevated C4a level is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% higher than the baseline C4a level. In some embodiments, the elevated C4a level is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-100%, 100%-200%, 200%-300%, 300%-400%, or 400%-500% higher than the baseline C4a level.

[0009] The elevated C4a / C4 ratio may be greater than the C4a / C4 ratio of a normal or healthy subject, such as a subject of similar age. In some embodiments, the elevated C4a / C4 ratio is greater than a reference C4a / C4 ratio. The reference C4a / C4 ratio may be equal to or greater than the median C4a / C4 ratio in samples from subjects with Huntington's disease, such as subjects of similar age. In other embodiments, the reference C4a / C4 ratio is equal to or greater than the 75th percentile C4a / C4 ratio in samples from normal or healthy subjects (subjects not suffering from Huntington's disease), such as subjects of similar age.

[0010] In some embodiments, the elevated C4a / C4 ratio is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the baseline C4a / C4 ratio. In some embodiments, the elevated C4a / C4 ratio is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-100%, 100%-200%, 200%-300%, 300%-400%, or 400%-500% greater than the baseline C4a / C4 ratio.

[0011] In some embodiments, the level of C4a or the C4a / C4 ratio is measured in cerebrospinal fluid (CSF) or plasma. In some embodiments, the subject has an elevated level of neurofilament light chain (NfL). The elevated NfL level can be higher than the NfL level of a normal or healthy subject, such as a subject of similar age. In some embodiments, the elevated NfL level is higher than the baseline NfL level. Baseline NfL levels are about 100pg / ml, 200pg / ml, 300pg / ml, 400pg / ml, 500pg / ml, 600pg / ml, 700pg / ml, 800pg / ml, 900pg / ml, 1000pg / ml, 1100pg / ml, 1200pg / ml, 1300pg / ml, 1400pg / ml, 1500pg / ml, 1600pg / ml, 1700pg / ml, 1800pg / ml, 1900pg / ml, or 2000pg / ml. In some embodiments, the elevated NfL level is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% higher than the NfL level of a normal or healthy subject or a reference NfL level. , 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1500%, 2000%, 2500%, 3000%, 3500%, 4000%, 4500%, or 5000% higher. In some embodiments, the elevated NfL level is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-10 ...30%-30%, 40%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 50%-30%, 50%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-90%, 10%-20% 0%-200%, 200%-300%, 300%-400%, 400%-500%, 500%-600%, 600%-700%, 700%-800%, 800%-900%, 900%-1000%, 1000%-2000%, 2000%-3000%, 3000%-4000%, or 4000%-5000% higher.In some embodiments, the level of NfL is measured in cerebrospinal fluid (CSF).

[0012] In other embodiments, the level of NfL is measured in plasma. Baseline NfL levels are about 1 pg / ml, 2 pg / ml, 3 pg / ml, 4 pg / ml, 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, 19 pg / ml, or 20 pg / ml. In some embodiments, the elevated NfL level is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% higher than the NfL level of a normal or healthy subject or a reference NfL level. , 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1500%, 2000%, 2500%, 3000%, 3500%, 4000%, 4500%, or 5000% higher. In some embodiments, the elevated NfL level is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-10 ...30%-30%, 40%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 50%-30%, 50%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-90%, 10%-20% 0%-200%, 200%-300%, 300%-400%, 400%-500%, 500%-600%, 600%-700%, 700%-800%, 800%-900%, 900%-1000%, 1000%-2000%, 2000%-3000%, 3000%-4000%, or 4000%-5000% higher.

[0013] In some embodiments, the inhibitor of the classical complement pathway is a C1q inhibitor, such as a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent. The antibody may be an anti-C1q antibody. The antibody may be administered at a dose of at least 5 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, or at least 100 mg / kg. In some embodiments, the antibody is administered at a dose of 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 105 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, or 150 mg / kg. In some embodiments, the antibody is administered at a dose of 75 mg / kg on days 1 and 5 or 6. In some embodiments, the antibody is further administered at a dose of 100 mg / kg every two weeks.

[0014] In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered weekly, biweekly, monthly, 6 weeks, or bimonthly. In some embodiments, the antibody is administered for at least 3 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. In some embodiments, the antibody is administered for 3 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0015] In some embodiments, the anti-C1q antibody may inhibit the interaction between C1q and autoantibodies, or between C1q and C1r, or between C1q and C1s, or promote the clearance of C1q from the circulation or tissues. In some embodiments, the antibody is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, an antibody fragment, or an antibody derivative thereof. The antibody fragment may be a Fab fragment, a Fab' fragment, a F(ab')2 fragment, an Fv fragment, a diabody, a single-chain antibody molecule, or a single-arm antibody molecule.

[0016] In some embodiments, the antibody comprises a light chain variable domain comprising HVR-L1 having the amino acid sequence of SEQ ID NO:5, HVR-L2 having the amino acid sequence of SEQ ID NO:6, and HVR-L3 having the amino acid sequence of SEQ ID NO:7, and a heavy chain variable domain comprising HVR-H1 having the amino acid sequence of SEQ ID NO:9, HVR-H2 having the amino acid sequence of SEQ ID NO:10, and HVR-H3 having the amino acid sequence of SEQ ID NO:11. In some embodiments, the antibody comprises a light chain variable domain comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from SEQ ID NOs:4 and 35-38, the light chain variable domain comprising HVR-L1 having the amino acid sequence of SEQ ID NO:5, HVR-L2 having the amino acid sequence of SEQ ID NO:6, and HVR-L3 having the amino acid sequence of SEQ ID NO:7, preferably the light chain variable domain comprises an amino acid sequence selected from SEQ ID NOs:4 and 35-38. In some embodiments, the antibody comprises a light chain variable domain comprising an amino acid sequence having at least about 95% homology to an amino acid sequence selected from SEQ ID NO: 8, and 31 to 34, and the heavy chain variable domain comprises HVR-H1 having the amino acid sequence of SEQ ID NO: 9, HVR-H2 having the amino acid sequence of SEQ ID NO: 10, and HVR-H3 having the amino acid sequence of SEQ ID NO: 11, preferably the heavy chain variable domain comprises an amino acid sequence selected from SEQ ID NO: 8, and 31 to 34. In some embodiments, the antibody fragment comprises a heavy chain Fab fragment of SEQ ID NO: 39 and a light chain Fab fragment of SEQ ID NO: 40.

[0017] In some embodiments, the inhibitor of the classical complement pathway is a C1r inhibitor, such as a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent, preferably an anti-C1r antibody. In some embodiments, the anti-C1r antibody inhibits the interaction between C1r and C1q or between C1r and C1s, or the anti-C1r antibody inhibits the catalytic activity of C1r or inhibits the processing of pro-C1r into active protease.

[0018] In some embodiments, the inhibitor of classical complement pathway is a C1s inhibitor, such as a small molecule, an antibody, an aptamer, an antisense nucleic acid or a gene editing agent, preferably an anti-C1s antibody.In some embodiments, the anti-C1s antibody inhibits the interaction between C1s and C1q, or between C1s and C1r, or between C1s and C2 or C4, or the anti-C1s antibody inhibits the catalytic activity of C1s, or inhibits the processing of pro-C1s into active protease, or binds to the activated form of C1s.In some embodiments, the antibody is stimulimab.

[0019] In some embodiments, the inhibitor of the classical complement pathway is an anti-C1 complex antibody, optionally which inhibits activation of C1r or C1s or blocks their ability to act on C2 or C4. The anti-C1 complex antibody binds to a combination epitope within the C1 complex, which combination epitope includes amino acids of both C1q and C1s, both C1q and C1r, both C1r and C1s, or each of C1q, C1r, and C1s.

[0020] In some embodiments, the inhibitor of the classical complement pathway is a C2 inhibitor, e.g., a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0021] In some embodiments, the inhibitor of the classical complement pathway is a C3 inhibitor, such as a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent. The C3 inhibitor can be APL-9 (Apellis) or AMY-101 (Amyndas).

[0022] In some embodiments, the inhibitor of the classical complement pathway is a C4 inhibitor, e.g., a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0023] In one aspect, disclosed herein is a method of treating Huntington's disease in a subject in need thereof. The method includes determining that the subject has elevated C4a levels or elevated C4a / C4 ratio. The method may further include administering to the subject an antibody having a light chain variable domain comprising the amino acid sequence of SEQ ID NO:37 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:33. In some embodiments, the antibody is administered intravenously at a dose of at least 75 mg / Kg on days 1 and 5 or 6. The antibody may further be administered intravenously at a dose of 100 mg / Kg every two weeks. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:14 and a light chain comprising the amino acid sequence of SEQ ID NO:40. [Brief description of the drawings]

[0024] [Figure 1] A and B show that inhibition of C1q blocks classical complement activation and provides synaptic protection in a preclinical animal model of HD. Figure 1A shows that inhibition of excess complement blockade inhibits deposition on synapses (fold change in complement deposition on synapses). Figure 1B shows that inhibition of excess complement protects against synapse loss (fold change in synapse number). [Diagram 2] 1 shows cerebrospinal fluid ("CSF") C4a rising and increasing with progression of HD. Data analyzed are from a natural history study. [Diagram 3] C4a is shown to be increased in the CSF of patients with manifest HD. The data analyzed are from the clinical trial in Example 2. [Figure 4A] FIG. 1 shows that neurofilament light ("NFL" or "Nfl") levels are significantly elevated in the CSF of patients with manifest HD and CSF NFL correlates with CSF C4a (HDClarity Study). FIG. 1 shows elevated NFL in the CSF of patients with manifest HD. [Figure 4B]We show that neurofilament light ("NFL" or "Nfl") levels are significantly elevated in the CSF of manifest HD patients and that CSF NFL correlates with CSF C4a (HDClarity Study). We show that CSF NFL correlates with CSF C4a. [Diagram 5] Shows that C4a can inform disease stage beyond prediction by age. Errors are residuals or incorrect categories created by the model. Each data point corresponds to one patient. Model LM1: HD disease stage predicted by age. Model LM2: HD disease stage predicted by age + C4a. LM2, which includes C4a in addition to age, predicts HD disease stage more accurately compared to LM1. The diagonal represents equal accuracy between the two models. Data below the diagonal shows that LM2 has lower error and therefore higher accuracy than LM1. [Figure 6] A and B show that a model combining complement activation, NfL, and age predicts HD stage more accurately than NfL alone. Figure 6A shows model HD progression predicted by NfL alone. Figure 6B shows model HD stage predicted by NfL, age, and complement. [Figure 7] A and B show that approximately 50% of HD patients have elevated CSF levels of the complement activation product C4a. Figure 7A shows elevated C4a in the CSF of natural history patients. Figure 7B shows a similar range of C4a in the current study cohort. [Figure 8] CSF C4a / C4 ratio: represents a sensitive measure of ongoing complement activation. C1q activation activity reduces (consumes) C4. C1q activation increases (produces) C4a. The C4a / C4 ratio corrects for genetic variability between subjects. [Figure 9] Figure 2 shows HD phase 2 data analyzed using CSF C4a / C4 ratio as a measure of ongoing complement activity. Patients divided into two groups based on baseline C4a / C4 levels. Characteristics of the two groups balanced at baseline. [Figure 10]We show that high baseline complement patients demonstrated consistent and significant improvements in cUHDRS over the 24-week treatment period. [Figure 11A] Figure 11A shows patients with high baseline C4a / C4 ratios consistently improved in cUHDRS subdomains over the 24-week treatment period: Figure 11A shows the Symbol Digit Modality Test (cognition). [Figure 11B] Figure 11B shows patients with high baseline C4a / C4 ratios who consistently improved in cUHDRS subdomains over the 24-week treatment period. Figure 11B shows total functional capacity (TFC, activities of daily living). [Figure 11C] Figure 11C shows that patients with high baseline C4a / C4 ratios consistently improved in cUHDRS subdomains over the 24-week treatment period. Figure 11C shows the Stroop Word Reading Test (SWR, cognition). [Figure 11D] Figure 11D shows total motor score (TMS) for patients with high baseline C4a / C4 ratios who consistently improved in cUHDRS subdomains over the 24-week treatment period. [Figure 12A] We show that 75% of patients with high baseline complement activity (C4a / C4) improved at week 24 on the cUHDRS compared to 36% with low activation. Biomarker differentiation responses are unlikely to be placebo driven. We show that 13 / 23 (56%) of all patients improved at week 24. [Figure 12B] We show that 75% of patients with high baseline complement activity (C4a / C4) improved at week 24 on the cUHDRS compared to 36% with low activation. Biomarker differentiation responses are unlikely to be placebo driven. We show that 9 / 12 (75%) patients improved with high baseline complement activation and 4 / 11 (36%) improved with low baseline complement activation. [Figure 13] Plasma NfL levels are consistent with the natural history of HD at 24 weeks. [Figure 14] Figure 1 shows that CSF NfL levels are consistent with the natural history of HD at 24 weeks. [Figure 15A]The combination of 24-week baseline C4a ratio, NfL, and age is shown to identify distinct groups of differential cUHDRS. Model predictions compared to the observed cUHDRS are shown. [Figure 15B] The combination of 24-week baseline C4a ratio, NfL, and age is shown to identify distinct groups of differential cUHDRS. Performance of patients by groups identified by the model is shown. Improvers are significantly higher than non-improvers. P-value = 0.009. Wilcoxon, one-sided test. [Figure 16A] It is shown that full-length C1q antibody demonstrated rapid, robust, and long-lasting complement engagement. Full-length C1q antibody levels in CSF are shown. Note: Since full-length C1q antibody concentrations <LLOQ are shown as 0.1 μg / mL, they are shown on a logarithmic scale. [Figure 16B] It is shown that full-length C1q antibody demonstrated rapid, robust, and long-lasting complement engagement. Complete engagement of C1q in CSF is shown. Note: Since C1q concentrations <LLOQ are shown as 0.25 μg / mL, they are shown on a logarithmic scale. *Data for discontinued subjects were included up to the point of discontinuation of dosing. [Figure 17A] It is shown that full-length C1q antibody demonstrated rapid, robust, and long-lasting complement engagement. Full-length C1q antibody levels in serum are shown. [Figure 17B] It is shown that full-length C1q antibody demonstrated rapid, robust, and long-lasting complement engagement. Complete engagement of C1q in serum is shown. Note: Since C1q concentrations <LLOQ are shown as 0.25 μg / mL, they are shown on a logarithmic scale. *Data for discontinued subjects were included up to the point of discontinuation of dosing. [Figure 18] The effect of full-length C1q antibody that persists through a 3-month treatment hiatus is shown. C4a release is a pharmacodynamic marker of C1q target engagement. [Figure 19]A and B show that full-length C1q antibody treatment led to early and sustained improvement in patients with excessive baseline complement activity (compare higher C4a / C4 vs lower C4a / C4 groups at week 24). Figure 19A shows Unified Huntington's Disease Rating Scale (cUHDRS). Figure 19B shows Total Functional Capacity (TFC, activities of daily living). *MMRM; LS means + / - 95% CI. Natural history interpolated from Schobel 2017 (TRACK-HD). [Figure 20A] Figure 20 shows that benefit in patients with higher complement activity was demonstrated across most cUHDRS component domains. Figure 20A shows total functional capacity (TFC, activities of daily living). *MMRM; LS means + / - 95% CI. Compare higher vs lower groups at week 24. N=23. [Figure 20B] Figure 20 shows that the benefit in patients with higher complement activity was demonstrated across most cUHDRS component domains. Figure 20B shows the Symbol Digit Modalities Test (SDMT, cognition). *MMRM; LS means + / - 95% CI. Compare higher vs lower groups at week 24. N=23. [Figure 20C] Figure 20 shows that benefit in patients with higher complement activity was demonstrated across most cUHDRS component domains. Figure 20C shows total motor score (TMS). Figure 20D shows Stroop Word Reading Test (SWR, cognition). *MMRM; LS means + / - 95% CI. Compare higher vs lower groups at week 24. N=23. [Figure 20D] Figure 20 shows that the benefit in patients with high complement activity was demonstrated across most cUHDRS component domains. Figure 20D shows the Stroop Word Reading Test (SWR, cognition). *MMRM; LS means + / - 95% CI. Compare higher vs lower groups at week 24. N=23. [Figure 21] Plasma NfL levels are consistent with the natural history of HD at 36 weeks with a 4% change from screening. [Figure 22]CSF NfL levels are consistent with the natural history of HD at week 36 with a 16% change from screening. *Results are independent of baseline complement activity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] This description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention. The section titles and overall organization of the specification are for convenience only and are not intended to limit the invention.

[0026] Complement activation is involved in the abnormal removal of synapses during neurodegenerative diseases and, together with its associated inflammation, may contribute to ongoing neuronal loss. Complement expression and activation are elevated in many neurodegenerative diseases, including HD, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) patients. Therapies targeting the complement pathway may inhibit complement-driven functional synapse loss and neuronal damage in HD and reduce disease progression.

[0027] In HD and other neurodegenerative diseases, synaptic dysfunction and elimination precede the axonal and neuronal loss associated with NfL release. Complement activation and synaptic dysfunction and elimination correlate with early and progressive functional decline throughout the disease process. Inhibition of C1q blocks classical complement activation and provides synaptic protection in preclinical models of HD. Inhibition of excess complement blocks deposition on synapses (Figure 1A). Inhibition of excess complement protects against synaptic loss (Figure 1B).

[0028] The present disclosure presents a model that evaluates complement activation, alone or in combination with NfL and age, and predicts HD stage more accurately than NfL alone or in combination with age. Data from HD clinical trials (Example 2) demonstrate that patients identified by using a model that evaluates high C4a levels and / or high C4a / C4 ratios show clinical improvement with anti-C1q antibody treatment. Clinical trial data also demonstrate that treatment with full-length anti-C1q antibodies provides clinical benefit to HD patients identified by using a model that evaluates complement activation, alone or in combination with NfL and age. Clinical trial data also demonstrate that taking into account complement activation, NfL, and age, and using full-length anti-C1q antibodies provides a robust clinical benefit to HD patients. Clinical benefit was measured by the composite Unified Huntington's Disease Rating Scale (cUHDRS) or one of the following domains: cognition (SDMT, SWR), total functional capacity (TFC), and total motor capacity (TMS) (Kieburtz K., Mov Disord., 1996 Mar;11(2):136-42 and Schobel SA, et al., Neurology. 2017 Dec 12;89(24):2495-2502).

[0029] The present disclosure generally relates to a method of treating Huntington's disease in a subject in need thereof, the method comprising determining that the subject has an elevated C4a level or an elevated C4a / C4 ratio, and administering to the subject so identified an inhibitor of the classical complement pathway.

[0030] All sequences set forth in this disclosure are incorporated by reference from U.S. Patent No. 10,316,0811, U.S. Patent Application No. 14 / 890,811, U.S. Patent No. 8,877,197, U.S. Patent No. 9,708,394, U.S. Patent Application No. 15 / 360,549, U.S. Patent No. 9,562,106, U.S. Patent No. 10,450,382, U.S. Patent No. 10,457,745, and International Patent Application No. PCT / US2018 / 022462, each of which is incorporated by reference herein for the disclosed antibodies and related compositions.

[0031] definition As used herein, "a" or "an" can mean one or more. As used herein in a claim(s), when used in conjunction with the term "comprising," the term "a" or "an" can mean one or more. For example, a reference to an "antibody" is a reference to one to many antibodies. As used herein, "another" can mean at least a second or more.

[0032] "Reference level" as used herein refers to a predetermined standard used as a standard for evaluating values ​​or data obtained from samples obtained from an individual. Reference level can be an absolute value, a relative value, a value with upper or lower limits, a range of values, an average value, a median value, a mean value, or a value compared to a particular control or baseline value. Reference level can be based on individual sample values, such as values ​​obtained from samples from the subject being tested, but at an earlier time point. Reference level can be based on multiple samples, for example, from a population of subjects of similar chronological age, sex, disease state, or otherwise matched group, or based on a pool of samples that includes or excludes the sample being tested. Reference level can also be determined from a representative number of samples (e.g., plasma or CSF) from different individuals affected by HD. Reference level can also be determined from biological samples from individuals not affected by HD (i.e., normal or healthy subjects of similar age). These biological samples from individuals with or without HD can include, for example, tissue biopsies, blood, plasma, serum, fecal samples, urine, cerebrospinal fluid, pap smears, or semen. A representative sample can include measurements from at least 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000 or more individuals.

[0033] The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody." The term "antibody" is used herein in the broadest sense and specifically includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, antibody fragments, so long as they exhibit biological activity, and antibody derivatives.

[0034] The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. H and V L When these two peptides are paired together, they form a single antigen-binding site. For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0035] L chains from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domain. Depending on the amino acid sequence of the constant domain (CH) of their heavy chains, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and are described generally in, for example, Abbas et al., Cellular and Molecular Immunology, 4th ed. (WB Saunders Co., 2000).

[0036] The term "drug" as used herein describes any molecule, e.g., protein or pharmaceutical, that has the ability to modulate synapse loss, particularly via the complement pathway. Candidate drugs also include genetic elements, e.g., antisense and RNAi molecules that inhibit C1q expression, as well as constructs that code for complement inhibitors, e.g., CD59, and the like. Candidate drugs encompass many chemical classes, but are typically organic molecules, including small organic compounds with molecular weights greater than 50 Daltons and less than 2500 Daltons. Candidate drugs contain functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically contain at least one amine, carbonyl, hydroxyl, or carboxyl group, and preferably at least two of these chemical functional groups. Candidate drugs often contain cyclic carbon or heterocyclic structures and / or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate drugs are also found among biomolecules, including peptides, sugars, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof. Generally, multiple assay mixtures are run in parallel at different drug concentrations to obtain differential responses to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e., at zero concentration or below the level of detection.

[0037] The "variable region" or "variable domain" of an antibody refers to the amino-terminal domains of the heavy or light chain of an antibody. The heavy and light chain variable domains are respectively referred to as "V H " and "V L These domains are generally the most variable parts of an antibody (relative to other antibodies of the same class) and contain the antigen-binding sites.

[0038] The term "variable" refers to the fact that certain segments of the variable domains vary widely in sequence from one antibody to another. The V domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, variability is not evenly distributed throughout the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in both the light and heavy chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Natural heavy and light chain variable domains each contain four FR regions that largely adopt a beta-sheet configuration connected by three HVRs that form loops that connect and, in some cases, form part of the beta-sheet structure. The HVRs within each chain are held in close proximity to each other by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0039] As used herein, the term "CDR" or "complementarity determining region" is intended to mean the non-contiguous antigen-binding sites found within the variable regions of heavy and light chain polypeptides. CDRs are described by Kabat et al., J. Biol. Chem. 252:6609-6616 (1977), Kabat et al., USDept. of Health and Human Services, "Sequences of proteins of immunological interest" (1991) (also referred to herein as Kabat 1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987) (also referred to herein as Chothia 1987), and MacCallum et al., J. Mol. Biol. 262:732-745 (1996), and the definition includes overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or grafted antibody or variants thereof is intended to be within the scope of the term as defined and used herein.

[0040] As used herein, the terms "CDR-L1", "CDR-L2", and "CDR-L3" refer to the first, second, and third CDRs, respectively, in a light chain variable region. As used herein, the terms "CDR-H1", "CDR-H2", and "CDR-H3" refer to the first, second, and third CDRs, respectively, in a heavy chain variable region. As used herein, the terms "CDR-1", "CDR-2", and "CDR-3" refer to the first, second, and third CDRs, respectively, in the variable region of either chain.

[0041] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogenous antibodies, i.e., the individual antibodies of the population are identical except for naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation) that may be present in minor amounts. Monoclonal antibodies are highly specific and directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous because they are typically synthesized by hybridoma culture and are uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as obtained as a substantially homogenous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present disclosure can be produced using, for example, hybridoma methods (e.g., Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2d ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567), phage-display techniques (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al., Nature, 352:624-628 (1991)), and the like. al., J.Mol.Biol.222:581-597(1992), Sidhu et al.,J.Mol.Biol.338(2):299-310(2004), Lee et al.,J.Mol.Biol.340(5):1073-1093(2004), Fellouse,Proc.Nat'l Acad.Sci.USA 101(34):12467-472 (2004), and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004), as well as techniques for producing human or human-like antibodies in animals having some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO1998 / 24893, WO1996 / 34096, WO1996 / 33735, WO1991 / 10741, Jakobovits et al., Proc. Nat'l Acad. Sci. USA 90:2551 (1993), Jakobovits et al., Nature 362:255-258 (1993), Bruggemann et al., Year in Immunol. 7:33 (1993), U.S. Patent Nos. 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, and 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992), Lonberg et al., Nature 368:856-859 (1994), Morrison, Nature 368:812-813 (1994), Fishwild et al., Nature Biotechnol. 14:845-851 (1996), Neuberger, Nature Biotechnol. 14:826 (1996), and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995).

[0042] A "full-length antibody" is usually a heterotetrameric glycoprotein of about 150,000 daltons comprising two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains at one end a variable domain (V H) followed by several constant domains. Each light chain has a variable domain (V L ) at its other end and a constant domain, with the light chain constant domain aligned with the first constant domain of the heavy chain and the light chain variable domain aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain variable domain and the heavy chain variable domain.

[0043] The terms "full length antibody," "intact antibody," and "complete antibody" are used interchangeably to refer to an antibody in substantially intact form, as opposed to an antibody fragment or antibody derivative. In particular, complete antibodies include those having heavy and light chains, including the Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions.

[0044] An "antibody fragment" or "functional fragment" of an antibody comprises a portion of an intact antibody, preferably the F region of an antibody that retains or has the antigen-binding and / or variable regions of the intact antibody or modified FcR binding ability. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments; diabodies; and linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)). Additional examples of antibody fragments include antibody derivatives, such as single-chain antibody molecules, single-arm antibodies, antibodies with a single antigen-binding arm, univalent antibodies, and multispecific antibodies formed from antibody fragments.

[0045] The term "single-arm antibody" herein is used to cover an antibody that comprises a single antigen-binding arm. A single-arm antibody may comprise an antigen-binding arm and an Fc region, the single antigen-binding arm comprising a light chain variable domain and a heavy chain variable domain, and the Fc region comprising a complex of a first and a second Fc polypeptide. In some embodiments, one of the Fc polypeptides, but not both, is an N-terminally truncated heavy chain. In some embodiments, the antibody may be a bivalent antibody, with one arm binding C1q and the other arm binding a different antigen. In response to other antigens, such antibodies do not crosslink and activate C1q.

[0046] An "antibody with a single antigen-binding arm," as used herein, refers to an antibody comprising a single antigen-binding arm and an Fc region, where the antigen-binding arm comprises a light chain variable domain and a heavy chain variable domain. In some embodiments, the antibody further comprises an inactive antigen-binding arm that is unable to bind to the antigen, or comprises an arm that binds to a different antigen. In some embodiments, the Fc region comprises a complex of a first Fc polypeptide and a second Fc polypeptide.

[0047] An "antibody derivative" is any construct that contains the antigen-binding region of an antibody. Examples of antibody derivatives include single-chain antibody molecules, single-arm antibodies, antibodies with a single antigen-binding arm, univalent antibodies, and multispecific antibodies formed from antibody fragments.

[0048] Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and one residual "Fc" fragment, a designation reflecting the ability to crystallize readily. The Fab fragment contains the entire L chain plus the variable region domain of the H chain (V H ), and the first constant domain of one heavy chain (C H1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide-linked Fab fragments with different antigen-binding activities and are still capable of cross-linking antigen. The Fab' fragment is H F(ab')2 antibody fragments differ from Fab fragments by having several additional residues at the carboxy terminus of one domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0049] The Fc fragment contains the carboxy termini of both H chains held together by disulfides. The effector functions of the antibody are determined by sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain cell types.

[0050] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain and includes native sequence Fc regions and variant Fc regions. Although the boundaries of an immunoglobulin heavy chain Fc region can vary, the human IgG heavy chain Fc region is usually defined as extending from the amino acid residue at position Cys226, or from Pro230, to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition may include an antibody population with all K447 residues removed, an antibody population without the K447 residue removed, and an antibody population with a mixture of antibodies with and without the K447 residue. Native sequence Fc regions suitable for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0051] A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes), native sequence human IgG2 Fc regions, native sequence human IgG3 Fc regions, and native sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0052] A "variant Fc region" comprises an amino acid sequence that differs from that of a native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or the Fc region of a parent polypeptide, e.g., from about 1 to about 10 amino acid substitutions in the native sequence Fc region or in the Fc region of the parent polypeptide, and preferably from about 1 to about 5 amino acid substitutions. A variant Fc region herein preferably retains at least about 80% homology with a native sequence Fc region and / or the Fc region of a parent polypeptide, and most preferably at least about 90% homology therewith, and more preferably at least about 95% homology therewith.

[0053] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Moreover, a preferred FcR binds an IgG antibody (gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors, where FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif ("ITIM") in its cytoplasmic domain. (See, e.g., M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991), Capel et al., Immunomethods 4:25-34 (1994), and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies.

[0054] The in vivo binding to FcRn and serum half-life of human FcRn high affinity binding polypeptides can be assayed, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which polypeptides having variant Fc regions are administered. WO2004 / 42072 (Presta) describes antibody variants with improved or reduced binding to FcR. See, for example, Shields et al., J.Biol.Chem.9(2):6591-6604(2001).

[0055] "Fv" is the minimum antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of one heavy chain variable region domain and one light chain variable region domain in tight non-covalent association. The folding of these two domains results in six hypervariable loops (three loops each from the H chain and L chain) that provide amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific HVRs) has the ability to recognize and bind to an antigen, albeit with a lower affinity than the entire binding site.

[0056] A "single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment comprising the VH and VL antibody domains connected in a single polypeptide chain. Preferably, the sFv polypeptide comprises a VH domain and a VL domain. H Domain and V L It further comprises a polypeptide linker between the domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0057] The term "diabody" refers to a diabody that is a peptide that binds V domains together to achieve inter-chain but not intra-chain V domain pairing, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. H Domain and V L This refers to small antibody fragments prepared by constructing sFv fragments (see previous paragraph) with a short linker (approximately 5-10 residues) between the domains. Bispecific diabodies are the VFv fragments of two antibodies. H and V LDiabodies are heterodimers of two "crossover" sFv fragments in which the domains are present on different polypeptide chains. Diabodies are described in more detail, for example, in EP 404,097, WO 1993 / 011161, WO / 2009 / 121948, WO / 2014 / 191493, Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[0058] As used herein, "chimeric antibody" refers to antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies of interest herein include PRIMATIZED® antibodies, in which the antigen-binding region of the antibody is derived from an antibody generated, for example, by immunizing macaque monkeys with the antigen of interest. As used herein, "humanized antibodies" are a subset of "chimeric antibodies."

[0059] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In some embodiments, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from an HVR of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications may be made to further improve antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence and all or substantially all of the FR regions correspond to those of a human immunoglobulin sequence, but the FR regions may include one or more individual FR residue substitutions which improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FRs typically will be no more than six in the H chain and no more than three in the L chain. The humanized antibody will also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986), Riechmann et al., Nature 332:323-329 (1988), and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998), Harris, Biochem. Soc. Transactions 23:1035-1038 (1995), Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994), and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0060] A "human antibody" is an antibody having an amino acid sequence that corresponds to that of an antibody produced by a human and / or produced using any of the techniques for producing human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. The methods described in Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenogeneic mice, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous loci have been disabled (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). See also Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006), for human antibodies generated by human B cell hybridoma technology.

[0061] As used herein, the term "hypervariable region", "HVR" or "HV" refers to a region of an antibody variable domain that is hypervariable in sequence and / or forms structurally defined loops. Generally, an antibody contains six HVRs, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). In natural antibodies, H3 and L3 exhibit the highest diversity among these six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, for example, Xu et al., Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct Biol. 3:733-736 (1996).

[0062] Several HVR delineations are in use and are encompassed herein. The Kabat complementarity determining regions (CDRs), HVRs, are based on sequence variability and are the most commonly used (Kabat et al., supra). Chothia, instead, refer to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The AbM HVRs represent a compromise between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are listed below. [Table 1]

[0063] HVRs may include "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL, and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) in VH. The variable domain residues are numbered according to Kabat et al. (supra) for each of these extended HVR definitions.

[0064] "Framework" or "FR" residues are those variable domain residues other than HVR residues as herein defined.

[0065] The phrases "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat", and variations thereof, refer to the numbering system used for the heavy or light chain variable domains of the compilation of antibodies in Kabat et al. (supra). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, the FR or HVR of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues may be determined for a given antibody by matching the sequence of the antibody with the "standard" Kabat numbered sequence at the regions of homology.

[0066] The Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally used when referring to residues in the immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Unless otherwise stated herein, references to residue numbers in the variable domain of an antibody refer to residue numbering according to the Kabat numbering system. Unless otherwise stated herein, references to residue numbers in the constant domain of an antibody refer to residue numbering according to the EU numbering system (see, e.g., U.S. Patent Publication No. 2010-280227).

[0067] An "acceptor human framework", as used herein, is a framework that comprises the amino acid sequence of a VL framework or a VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence as that, or it may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. If pre-existing amino acid changes are present in the VH, preferably those changes are present only at three, two, or one of positions 71H, 73H, and 78H, e.g., the amino acid residues at those positions may be 71A, 73T, and / or 78A. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0068] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is made from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for VL, the subgroup can be subgroup kappa I, kappa II, kappa III or kappa IV as in Kabat et al., supra. Additionally, for VH, the subgroup can be subgroup I, subgroup II or subgroup III as in Kabat et al., supra.

[0069] An "amino acid modification" at a specified position refers to a substitution or deletion of the specified residue, or an insertion of at least one amino acid residue adjacent to the specified residue. An insertion "adjacent to" a specified residue means an insertion within 1-2 residues thereof. The insertion may be on the N-terminal or C-terminal side of the specified residue. A preferred amino acid modification herein is a substitution.

[0070] An "affinity matured" antibody is one which has one or more changes in one or more HVRs thereof which result in an improvement in the affinity of the antibody for antigen compared to a parent antibody which does not have those change(s). In some embodiments, an affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of HVR and / or framework residues has been described, for example, by Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994), Schier et al. Gene 169:147-155 (1995), Yelton et al. J. Immunol. 155:1994-2004 (1995), Jackson et al., J. Immunol. 154(7):3310-9 (1995), and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0071] As used herein, the term "specifically recognize" or "specifically bind" refers to a measurable and reproducible interaction, such as attraction or binding, between a target and an antibody that determines the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody that specifically or preferentially binds to a target or epitope is an antibody that binds to this target or epitope with higher affinity, avidity, more readily, and / or with a longer duration than it binds to other targets or other epitopes of targets. For example, it is understood that an antibody (or moiety) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require exclusive binding (although it can include exclusive binding). An antibody that specifically binds to a target has at least about 10 3 M -1 or 10 4 M -1 , sometimes about 10 5 M -1 or 10 6 M -1 , and in other cases, about 10 6 M -1 or 10 7 M -1 , about 10 8 M -1 ~10 9 M -1 , or about 10 10 M -1 ~10 11 M -1 The antibody may have an association constant of 100 or more. A variety of immunoassay formats can be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. See, for example, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0072] "Identity," as used herein, indicates that the amino acid residue at any particular position in the aligned sequences is the same between the sequences. "Similarity," as used herein, indicates that the amino acid residue at any particular position in the aligned sequences is of a similar type between the sequences. For example, leucine can be substituted for isoleucine or valine. Other amino acids that can often be substituted for one another include: - phenylalanine, tyrosine and tryptophan (amino acids with aromatic side chains); - lysine, arginine and histidine (amino acids with basic side chains); -Aspartate and glutamate (amino acids with acidic side chains); - asparagine and glutamine (amino acids with amide side chains); and - Cysteine ​​and methionine (amino acids with sulfur-containing side chains), including but not limited to:

[0073] The degree of identity and similarity can be readily calculated (see, e.g., Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing. Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991).

[0074] As used herein, an "interaction" between a complement protein and a second protein includes, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, bonds, covalent bonds, and ionic bonds. As used herein, an antibody "inhibits an interaction" between two proteins if the antibody disrupts, reduces, or completely eliminates the interaction between the two proteins. An antibody of the present disclosure, or a fragment thereof, "inhibits an interaction" between two proteins if the antibody or a fragment thereof binds to one of the two proteins.

[0075] A "blocking," "antagonist," "inhibitory," or "neutralizing" antibody is an antibody that inhibits or reduces one or more biological activities of the antigen to which it binds, e.g., interaction with one or more proteins. In some embodiments, a blocking, antagonist, inhibitory, or "neutralizing" antibody substantially or completely inhibits one or more biological activities or interactions of an antigen.

[0076] The term "inhibitor" refers to a compound that has the ability to inhibit the biological function of a target biomolecule, e.g., an mRNA or a protein, whether by decreasing the activity or expression of the target biomolecule. An inhibitor can be an antibody, a small molecule, or a nucleic acid molecule. The term "antagonist" refers to a compound that binds to a receptor and blocks or attenuates the biological response of the receptor. The term "inhibitor" can also refer to an "antagonist."

[0077] Antibody "effector functions" refer to the biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary depending on the antibody isotype.

[0078] As used herein, the term "affinity" refers to the equilibrium constant for the reversible binding of two substances (e.g., an antibody and an antigen), expressed as the dissociation constant (KD). The affinity can be at least 1-fold higher, at least 2-fold higher, at least 3-fold higher, at least 4-fold higher, at least 5-fold higher, at least 6-fold higher, at least 7-fold higher, at least 8-fold higher, at least 9-fold higher, at least 10-fold higher, at least 20-fold higher, at least 30-fold higher, at least 40-fold higher, at least 50-fold higher, at least 60-fold higher, at least 70-fold higher, at least 80-fold higher, at least 90-fold higher, at least 100-fold higher, or at least 1,000-fold higher, or more, than the affinity of the antibody for an unrelated amino acid sequence. The affinity of the antibody for the target protein can be, for example, from about 100 nanomolar (nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM to about 1 femtomolar (fM), or more. As used herein, the term "avidity" refers to the resistance of a complex of two or more substances to dissociation upon dilution. The terms "immunoreactive" and "preferentially bind" are used interchangeably herein with respect to antibodies and / or antigen-binding fragments.

[0079] The term "binding" refers to a direct association between two molecules, for example, by covalent, electrostatic, hydrophobic, and ionic and / or hydrogen bonding interactions, including interactions such as salt bridges and water bridges. For example, a subject anti-C1s antibody specifically binds to an epitope within the complement C1s protein. "Specific binding" refers to binding that is at least about 10 -7 M or more, e.g., 5×10 -7 M, 10 -8 M, 5×10 -8 "Non-specific binding" refers to binding with an affinity of about 10 -7 Affinity of less than M, e.g., 10 -6 M, 10 -5 M, 10 -4 It refers to binding with an affinity of M or similar.

[0080] "k onThe term "rate constant" as used herein is intended to refer to the rate constant for the association of an antibody to an antigen.

[0081] "k off The term, as used herein, is intended to refer to the rate constant for dissociation of an antibody from the antibody / antigen complex.

[0082] "K D The term "as used herein" is intended to refer to the equilibrium dissociation constant of an antibody-antigen interaction.

[0083] As used herein, with respect to peptide, polypeptide, or antibody sequences, "percent (%) amino acid sequence identity" and "homology" refer to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps as necessary to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software, such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared.

[0084] A "biological sample" encompasses a variety of sample types obtained from an individual and may be used in diagnostic or monitoring assays. The definition encompasses blood and other liquid samples of biological origin, solid tissue samples, such as biopsy specimens or tissue cultures or cells derived therefrom, and their progeny. The definition also includes samples that have been manipulated in any way after their procurement, for example, by treatment with reagents, solubilization, or enrichment for certain components, such as polynucleotides. The term "biological sample" encompasses clinical samples, and also includes cultured cells, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples. The term "biological sample" includes urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, blood fractions, such as plasma and serum, and the like. The term "biological sample" also encompasses solid tissue samples, tissue culture samples, and cell samples.

[0085] "Host cell" includes an individual cell or cell culture that can be or has been a recipient for a vector(s) for incorporation of a polynucleotide insert. A host cell includes the progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, sudden, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of the present disclosure.

[0086] As used herein, "carrier" includes pharma- ceutically acceptable carriers, excipients, or stabilizers that are non-toxic to cells or mammals exposed thereto at the dosages and concentrations used. Often, physiologically acceptable carriers are aqueous pH buffers. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or non-ionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

[0087] The term "subject" as used herein refers to a living mammal and may be used interchangeably with the term "patient." Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates, such as chimpanzees, and other ape and monkey species; farm animals, such as cows, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. The term does not denote a particular age or sex.

[0088] As used herein, the term "treating" or "treatment" includes reducing, arresting, or reversing the symptoms, clinical signs, or underlying pathology of a condition, stabilizing or ameliorating the subject's condition, or reducing the likelihood that the subject's condition will worsen to the same extent as if the subject had not received treatment.

[0089] The term "therapeutically effective amount" of a compound in the context of a method of treating a subject refers to the amount of compound(s) in a preparation that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), relieves symptoms, ameliorates pathology, or delays the onset of a disease condition, for example, in accordance with clinically accepted standards for treating a disorder or condition, or for cosmetic purposes, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutically effective amount herein may vary depending on factors such as the disease state, age, sex, and weight of the patient, as well as the ability of the antibody to elicit a desired response in the individual.

[0090] As used herein, an individual "at risk" of developing a particular disease, disorder, or condition may or may not exhibit detectable disease or disease symptoms, and may or may not exhibit detectable disease or disease symptoms prior to the treatment methods described herein. "At risk," as known in the art, indicates that an individual has one or more risk factors, which are measurable parameters that correlate with the development of a particular disease, disorder, or condition. Individuals who have one or more of these risk factors are more likely to develop a particular disease, disorder, or condition than individuals who do not have one or more of these risk factors.

[0091] "Chronic" administration refers to administering an agent(s) continuously, as opposed to an acute mode, to maintain an initial therapeutic effect (activity) over an extended period of time. "Intermittent" administration refers to treatment that is not administered continuously without interruption, but rather is cyclic / periodic in nature.

[0092] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference, including, but not limited to, methods and / or materials related to which the publications are cited, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FMA Usubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR2: A Practical Approach (MJ MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (RI Freshney, ed. (1987)), Oligonucleotide Synthesis (MJ Gait, ed., 1984), Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual, 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Notebook (JECellis, ed., 1998) Academic Press; Animal Cell Culture (RIFreshney), ed., 1987), Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JBGriffiths, and D.G. Newell, eds., 1993-8), J. Wiley and Sons; Handbook of Experimental Immunology (DMWeir and CC Blackwell, eds.), Gene Transfer Vectors for Mammalian Cells (JMMiller and MP Calos, eds., 1987), PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994), Current Protocols in Immunology (JEColigan et al., eds., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (CA Janeway and P. Travers, 1997), Antibodies (P. Finch, 1997), Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989), Monoclonal Antibodies: A Practical The present invention discloses and explains widely used methodologies described in: Antibodies: A Laboratory Manual (P. Shepherd and C. Dean, eds., Oxford University Press, 2000), Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane, Cold Spring Harbor Laboratory Press, 1999), The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995), and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JBLippincott Company, 1993).

[0093] C1q inhibitors The inhibitor of the classical complement pathway may be a C1q inhibitor, for example, a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0094] The anti-C1q antibodies disclosed herein are potent inhibitors of C1q.

[0095] C1q is a large multimeric protein of 460 kDa consisting of 18 polypeptide chains (6 C1q A chains, 6 C1q B chains, and 6 C1q C chains). The C1r and C1s complement proteins bind to the C1q tail region to form the C1 complex (C1qr2s2).

[0096] Suitable inhibitors include complement factor C1q and / or antibodies that bind to C1q in the C1 complex of the classical complement activation pathway. The bound complement factor may be from any organism that has a complement system, including, but not limited to, any mammalian organism, such as human, mouse, rat, rabbit, monkey, dog, cat, cow, horse, camel, sheep, goat, or pig.

[0097] As used herein, a "C1 complex" refers to a protein complex that may include, but is not limited to, one C1q protein, two C1r proteins, and two C1s proteins (e.g., C1qr 2 s 2 )

[0098] As used herein, "complement factor C1q" refers to both the wild-type sequence and the naturally occurring variant sequence.

[0099] A non-limiting example of a complement factor C1q recognized by the antibodies of the present disclosure is human C1q, which comprises three polypeptide chains A, B, and C: C1q, chain A (Homo sapiens), accession number protein Database: NP_057075.1; GenBank number: NM_015991: >gi|7705753|ref|NP_057075.1|Complement C1q Subcomponent Subunit A Precursor [Homo sapiens] (SEQ ID NO:1) MEGPRGWLVLCVLAISLASMVTEDLCRAPDGKKGEAGRPGRRGRPGLKGEQGEPGAPGIRTGIQGLKGDQGEPGPSGNPGKVGYPGPSGPLGARGIPGIKGTKGSPGNIKDQPRPAFSAIRRN PPMGGNVVIFDTVITNQEEPYQNHSGRFVCTVPGYYYYFTFQVLSQWEICLSIVSSSSRGQVRRSLGFCDTTNKGLFQVVSGGMVLQLQQGDQVWVEKDPKKGHIYQGSEADSVFSGFLIFPSA. C1q, chain B (Homo sapiens), accession number protein Database: NP_000482.3; GenBank number: NM_000491.3: >gi|87298828|ref|NP_000482.3|Complement C1q Subcomponent Subunit B Precursor [Homo sapiens] (SEQ ID NO:41) MMMKIPWGSIPVLMLLLLGLIDISQAQLSCTGPPAIPGIPGIPGTPGPDGQPGTPGIKGEKGLPGLAGDHGEFGEKGDPGIPGNPGKVGPKGPMGPKGGPGAPGAPGPKGESGDYKATQKIAFSAT RTINVPLRRDQTIRFDHVITNMNNNYEPRSGKFTCKVPGLYYFTYHASSRGNLCVNLMRGRERAQKVVTFCDYAYNTFQVTTGGMVLKLEQGENVFLQATDKNSLLGMEGANSIFSGFLLFPDMEA. C1q, chain C (Homo sapiens), accession number protein Database: NP_001107573.1; GenBank number: NM_001114101.1: >gi|166235903|ref|NP_001107573.1|Complement C1q Subcomponent Subunit C Precursor [Homo sapiens] (SEQ ID NO:42) MDVGPSSLPHLGLKLLLLLLLLPLRGQANTGCYGIPGMPGLPGAPGKDGYDGLPGPKGEPGIPAIPGIRGPKGQKGEPGLPGHPGKNGPMGPGMPGVPGPMGIPGEPGEEGRYKQKFQSVFT VTRQTHQPPAPNSLIRFNAVLTNPQGDYDTSTGKFTCKVPGLYYFVYHASHTANLCVLLYRSGVKVVTFCGHTSKTNQVNSGGVLLRLQVGEEVWLAVNDYYDMVGIQGSDSVFSGFLLFPD.

[0100] Thus, an anti-C1q antibody of the disclosure may bind to polypeptide chain A, polypeptide chain B, and / or polypeptide chain C of a C1q protein. In some embodiments, an anti-C1q antibody of the disclosure binds to polypeptide chain A, polypeptide chain B, and / or polypeptide chain C of human C1q or a homolog thereof, e.g., mouse, rat, rabbit, monkey, dog, cat, cow, horse, camel, sheep, goat, or pig C1q. In some embodiments, the anti-C1q antibody is a human antibody, a humanized antibody, or a chimeric antibody.

[0101] Other anti-C1q antibodies suitable for binding to C1q protein are known in the art, e.g., antibody catalog numbers: AF2379, AF1696, MAB1696, and MAB23791 (R&D System), NBP1-87492, NB100-64420, H00000712-B01P, H00000712-D01P, and H00000712-D01 (Novus Biologicals), MA1-83963, MA1-40311, PA5-14208, PA5-29586, and PA1-36177 (ThermoFisher). Scientific), ab71940, ab11861, ab4223, ab72355, ab182451, ab46191, ab227072, ab182940, ab216979, and ab235454 (Abcam). In addition, multiple siRNA, shRNA, CRISPR constructs for reducing C1q expression, such as SiRNA products #sc-43651, sc-44962, sc-105153, sc-141842, ShRNA products #sc-43651-SH, sc-43651-V, sc-44962-SH, sc-44962-V, sc-105153-SH, sc-105153-V, sc-141842-SH, sc-141842-V, CRI SPR product #s sc-419385, sc-419385-HDR, sc-419385-NIC, sc-419385-NIC-2, sc-402156, sc-402156-KO-2, sc-404309, sc-404309-HDR, sc-404309-NIC, sc-404309-NIC-2, sc-419386, sc-419386-HDR, sc-419386-NIC, sc-419386-NIC-2 (e.g., Santa Cruz Biotechnology) can be found in the commercially available product listings of the companies referenced above.

[0102] Light and heavy chain hypervariable region and variable domain sequences of antibody M1 (incorporated by reference from U.S. Pat. No. 9,708,394) The nucleic acid and amino acid sequences encoding the light chain variable and heavy chain variable domains of antibody M1 were determined using standard techniques. The amino acid sequence of the light chain variable domain of antibody M1 is:

[0103] The file is TIFF2025503545000002.tif23170.

[0104] The hypervariable regions (HVRs) of the light chain variable domains are shown in bold and underlined text. In some embodiments, HVR-L1 of the M1 light chain variable domain has the sequence RASKSINKYLA (SEQ ID NO:5), HVR-L2 of the M1 light chain variable domain has the sequence SGSTLQS (SEQ ID NO:6), and HVR-L3 of the M1 light chain variable domain has the sequence QQHNEYPLT (SEQ ID NO:7).

[0105] The amino acid sequence of the heavy chain variable domain of antibody M1 is

[0106] The file is TIFF2025503545000003.tif33170.

[0107] The hypervariable regions (HVRs) of the heavy chain variable domains are shown in bold and underlined text. In some embodiments, HVR-H1 of the M1 heavy chain variable domain has the sequence GYHFTSYWMH (SEQ ID NO:9), HVR-H2 of the M1 heavy chain variable domain has the sequence VIHPNSGSINYNEKFES (SEQ ID NO:10), and HVR-H3 of the M1 heavy chain variable domain has the sequence ERDSTEVLPMDY (SEQ ID NO:11).

[0108] The nucleic acid sequence encoding the light chain variable domain is GATGTCCAGATAACCCAGTCTCCATCTTATCTTGCTGCATCTCCTGGAGAAACCATTACTATTAATTGCAGGGCAAGTAAGAGCATTAACAAATATTTAGCCTGGTATCAAGAGAAACCTGGGAAAACTAATAAGCTTCTTATCTACTCTGGATCCACTTTGCAATC It was determined that TGGAATTCCATCAAGGTTCAGTGGCAGTGGATCTGGTACAGATTTCACTCTCACCATCAGTAGCCTGGAGCCTGAAGATTTTGCAATGTATTACTGTCAACAACATAATGAATACCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA (SEQ ID NO: 12).

[0109] The nucleic acid sequence encoding the heavy chain variable domain is CAGGTCCAACTGCAGCAGCCTGGGGCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAAGTTGTCCTGCAAGTCTTCTGGCTACCATTTCACCAGCTACTGGATGCACTGGGTGAAGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGAGTGATTCATCCTAATAGTGGTAGTATTAACTACAATGAGAA It was determined that GTTCGAGAGCAAGGCCACACTGACTGTAGACAAATCCTCCAGCACAGCCTACATGCAACTCAGCAGCCTGACATCTGAGGACTCGGCGGTCTATTATTGTGCAGGAGAGAGAGATTCTACGGAGGTTCTCCCTATGGACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 13).

[0110] Deposit of materials The following materials have been deposited pursuant to the Budapest Treaty at the American Type Culture Collection, ATCC Patent Depository, 10801 University Blvd., Manassas, Va. 20110-2209, USA (ATCC). [Table 2]

[0111] A hybridoma cell line (mouse hybridoma C1qM1 7788-1(M)051613) producing the M1 antibody has been deposited with the ATCC under conditions ensuring that access to the culture will be available during the pendency of the patent application and for 30 years, or 5 years after the latest claim, or until the life of the patent, whichever is longer. The deposit will be replaced if it becomes non-viable during that time. The deposit will be available as required by foreign patent laws in countries in which counterpart applications of this application, or progeny thereof, are filed. It should be understood, however, that the availability of the deposit does not constitute a license to practice the invention in derogation from patent rights granted by governmental action.

[0112] Disclosed herein is a method of administering an anti-C1q antibody comprising a light chain variable domain and a heavy chain variable domain. The antibody can bind at least human C1q, mouse C1q, or rat C1q. The antibody can be a humanized antibody, a chimeric antibody, or a human antibody. The antibody can be a monoclonal antibody, an antibody fragment thereof, and / or an antibody derivative thereof. The light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody M1 produced by the hybridoma cell line deposited under ATCC Accession No. PTA-120399. The heavy chain variable domain comprises HVR-H1, HVR-H2, and HVR-H3 of monoclonal antibody M1 produced by the hybridoma cell line deposited under ATCC Accession No. PTA-120399.

[0113] In some embodiments, the amino acid sequences of the light chain variable domain and the heavy chain variable domain comprise one or more of SEQ ID NO:5 for HVR-L1, SEQ ID NO:6 for HVR-L2, SEQ ID NO:7 for HVR-L3, SEQ ID NO:9 for HVR-H1, SEQ ID NO:10 for HVR-H2, and SEQ ID NO:11 for HVR-H3.

[0114] The antibody may comprise a light chain variable domain amino acid sequence at least 85%, 90%, or 95% identical to SEQ ID NO:4, preferably retaining HVR-L1 RASKSINKYLA (SEQ ID NO:5), HVR-L2 SGSTLQS (SEQ ID NO:6), and HVR-L3 QQHNEYPLT (SEQ ID NO:7). The antibody may comprise a heavy chain variable domain amino acid sequence at least 85%, 90%, or 95% identical to SEQ ID NO:8, preferably retaining HVR-H1 GYHFTSYWMH (SEQ ID NO:9), HVR-H2 VIHPNSGSINYNEKFES (SEQ ID NO:10), and HVR-H3 ERDSTEVLPMDY (SEQ ID NO:11).

[0115] Disclosed herein is a method for administering an anti-C1q antibody that inhibits the interaction between C1q and autoantibodies. In a preferred embodiment, the anti-C1q antibody causes the clearance of C1q from the circulation or tissues.

[0116] In some embodiments, the anti-C1q antibodies of the present disclosure inhibit the interaction between C1q and C1s. In some embodiments, the anti-C1q antibodies inhibit the interaction between C1q and C1r. In some embodiments, the anti-C1q antibodies inhibit the interaction between C1q and C1s and between C1q and C1r. In some embodiments, the anti-C1q antibodies inhibit the interaction between C1q and another antibody, e.g., an autoantibody. In preferred embodiments, the anti-C1q antibodies cause the clearance of C1q from the circulation or tissues. In some embodiments, the anti-C1q antibodies inhibit the respective interactions with a stoichiometry of less than 2.5:1, 2.0:1, 1.5:1, or 1.0:1. In some embodiments, the C1q antibodies inhibit interactions such as the C1q-C1s interaction at approximately equimolar concentrations of C1q and anti-C1q antibodies. In other embodiments, the anti-C1q antibody is less than 20:1, less than 19.5:1, less than 19:1, less than 18.5:1, less than 18:1, less than 17.5:1, less than 17:1, less than 16.5:1, less than 16:1, less than 15.5:1, less than 15:1, less than 14.5:1, less than 14:1, less than 13.5:1, less than 13:1, less than 12.5:1, less than 12:1, less than 11.5:1, less than 11:1 , 10.5:1, 10:1, 9.5:1, 9:1, 8.5:1, 8:1, 7.5:1, 7:1, 6.5:1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2.0:1, 1.5:1, or 1.0:1. In certain embodiments, the anti-C1q antibody binds to C1q with a binding stoichiometry ranging from 20:1 to 1.0:1 or less than 1.0:1. In certain embodiments, the anti-C1q antibody binds to C1q with a binding stoichiometry ranging from 6:1 to 1.0:1 or less than 1.0:1. In certain embodiments, anti-C1q antibodies bind to C1q with a binding stoichiometry ranging from 2.5:1 to 1.0:1 or less than 1.0:1. In some embodiments, anti-C1q antibodies inhibit the interaction between C1q and C1r, or between C1q and C1s, or between C1q and both C1r and C1s.In some embodiments, the anti-C1q antibody inhibits the interaction between C1q and C1r, between C1q and C1s, and / or between C1q and both C1r and C1s. In some embodiments, the anti-C1q antibody binds to the A chain of C1q. In other embodiments, the anti-C1q antibody binds to the B chain of C1q. In other embodiments, the anti-C1q antibody binds to the C chain of C1q. In some embodiments, the anti-C1q antibody binds to the A chain of C1q, the B chain of C1q, and / or the C chain of C1q. In some embodiments, the anti-C1q antibody binds to the globular domain of the A chain, the B chain, and / or the C chain of C1q. In other embodiments, the anti-C1q antibody binds to the collagen-like domain of the A chain, the B chain, and / or the C chain of C1q.

[0117] Where an antibody of the disclosure inhibits an interaction between two or more complement factors, e.g., the interaction of C1q and C1s or the interaction between C1q and C1r, the interaction that occurs in the presence of the antibody may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% compared to a control in which an antibody of the disclosure is not present. In certain embodiments, the interaction that occurs in the presence of the antibody is reduced by an amount ranging from at least 30% to at least 99% compared to a control in which an antibody of the disclosure is not present.

[0118] In some embodiments, an antibody of the present disclosure inhibits C2 or C4 cleavage by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%, or an amount ranging from at least 30% to at least 99%, compared to a control in which no antibody of the present disclosure is present. Methods for measuring C2 or C4 cleavage are well known in the art. The EC of an antibody of the present disclosure with respect to C2 or C4 cleavage can be determined by the following methods: 50Values ​​may be less than 3 μg / ml, 2.5 μg / ml, 2.0 μg / ml, 1.5 μg / ml, 1.0 μg / ml, 0.5 μg / ml, 0.25 μg / ml, 0.1 μg / ml, 0.05 μg / ml, In some embodiments, the antibodies of the disclosure inhibit C2 or C4 cleavage at approximately equimolar concentrations of C1q and the respective anti-C1q antibodies.

[0119] In some embodiments, an antibody of the disclosure inhibits autoantibody- and complement-dependent cytotoxicity (CDC) by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%, or an amount ranging from at least 30% to at least 99%, relative to a control lacking the antibody of the disclosure. 50 Values ​​can be less than 3 μg / ml, 2.5 μg / ml, 2.0 μg / ml, 1.5 μg / ml, 1.0 μg / ml, 0.5 μg / ml, 0.25 μg / ml, 0.1 μg / ml, 0.05 μg / ml.

[0120] In some embodiments, the antibodies of the present disclosure inhibit complement-dependent cell-mediated cytotoxicity (CDCC) by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%, or an amount ranging from at least 30% to at least 99%, relative to a control lacking the antibody of the present disclosure. Methods for measuring CDCC are well known in the art. With respect to CDCC inhibition, the EC 50 Values ​​may be less than 3 μg / ml, 2.5 μg / ml, 2.0 μg / ml, 1.5 μg / ml, 1.0 μg / ml, 0.5 μg / ml, 0.25 μg / ml, 0.1 μg / ml, 0.05 μg / ml, In some embodiments, the antibodies of the disclosure inhibit CDCC but do not inhibit antibody-dependent cellular cytotoxicity (ADCC).

[0121] Humanized Anti-Complement C1q Antibody (Incorporated by reference from U.S. Pat. No. 10,316,081) The humanized antibodies of the present disclosure specifically bind to complement factor C1q and / or C1q protein in the C1 complex of the classical complement pathway. The humanized anti-C1q antibodies may specifically bind to human C1q, human and mouse C1q, rat C1q, or human C1q, mouse C1q, and rat C1q.

[0122] In some embodiments, the human heavy chain constant region is a human IgG4 heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 47 or an amino acid sequence having at least 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% homology to SEQ ID NO: 47. The human IgG4 heavy chain constant region may comprise an Fc region having one or more modifications and / or amino acid substitutions according to Kabat numbering. In such cases, the Fc region comprises an amino acid substitution of leucine to glutamate at position 248 (corresponding to the L115E mutation in IgG4), such a substitution inhibits the Fc region from interacting with an Fc receptor. In some embodiments, the Fc region comprises an amino acid substitution of serine to proline at position 241 (corresponding to S108P in IgG4), such a substitution prevents arm switching in the antibody.

[0123] The amino acid sequence of the human IgG4 (S241P L248E; corresponding to S108P and L115E of SEQ ID NO: 47) heavy chain constant domain is: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 47)

[0124] The antibody may comprise a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence selected from any one of SEQ ID NOs: 31-34, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from any one of SEQ ID NOs: 31-34. In certain such embodiments, the light chain variable domain comprises an amino acid sequence selected from any one of SEQ ID NOs: 35-38, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from any one of SEQ ID NOs: 35-38.

[0125] The amino acid sequence of the heavy chain variable domain variant 1 (VH1) is as follows:

[0126] TIFF2025503545000005.tif39170The hypervariable regions (HVRs) of VH1 are shown in bold and underlined text.

[0127] The amino acid sequence of heavy chain variable domain variant 2 is:

[0128] TIFF2025503545000006.tif33170 Hypervariable regions (HVRs) of VH2 are shown in bold and underlined text.

[0129] The amino acid sequence of the heavy chain variable domain variant 3 (VH3) is as follows:

[0130] TIFF2025503545000007.tif39170The hypervariable regions (HVRs) of VH3 are shown in bold and underlined text.

[0131] The amino acid sequence of the heavy chain variable domain variant 4 (VH4) is as follows:

[0132] TIFF2025503545000008.tif39170The hypervariable regions (HVRs) of VH4 are shown in bold and underlined text.

[0133] The amino acid sequence of the kappa light chain variable domain variant 1 (Vκ1) is:

[0134] TIFF2025503545000009.tif29170The hypervariable regions (HVRs) of Vκ1 are shown in bold and underlined text.

[0135] The amino acid sequence of the kappa light chain variable domain variant 2 (Vκ2) is:

[0136] TIFF2025503545000010.tif29170The hypervariable regions (HVRs) of Vκ2 are shown in bold and underlined text.

[0137] The amino acid sequence of the kappa light chain variable domain variant 3 (Vκ3) is:

[0138] TIFF2025503545000011.tif29170The hypervariable regions (HVRs) of Vκ3 are shown in bold and underlined text.

[0139] The amino acid sequence of the kappa light chain variable domain variant 4 (Vκ4) is:

[0140] TIFF2025503545000012.tif29170The hypervariable regions (HVRs) of Vκ4 are shown in bold and underlined text.

[0141] The antibody may comprise a light chain variable domain amino acid sequence that is at least 85%, 90%, or 95% identical to SEQ ID NOs: 35-38, while retaining HVR-L1 RASKSINKYLA (SEQ ID NO: 5), HVR-L2 SGSTLQS (SEQ ID NO: 6), and HVR-L3 QQHNEYPLT (SEQ ID NO: 7). The antibody may comprise a heavy chain variable domain amino acid sequence that is at least 85%, 90%, or 95% identical to SEQ ID NOs: 31-34, while retaining preferably HVR-H1 GYHFTSYWMH (SEQ ID NO: 9), HVR-H2 VIHPNSGSINYNEKFES (SEQ ID NO: 10), and HVR-H3 ERDSTEVLPMDY (SEQ ID NO: 11).

[0142] The antibody can comprise a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:14 and the light chain comprises the amino acid sequence of SEQ ID NO:40.

[0143] The amino acid sequence of the heavy chain is:

[0144] TIFF2025503545000013.tif77170The hypervariable regions (HVRs) of VH3 are shown in bold and underlined text.

[0145] The amino acid sequence of the light chain is:

[0146] TIFF2025503545000014.tif39170

[0147] The complementarity determining regions (CDRs) of SEQ ID NO:40 are shown in bold and underlined text.

[0148] In some embodiments, a humanized anti-C1q antibody of the present disclosure comprises a heavy chain variable region containing a Fab region and a heavy chain constant region containing an Fc region, wherein the Fab region specifically binds to a C1q protein of the present disclosure, while the Fc region is incapable of binding to a C1q protein. In some embodiments, the Fc region is derived from a human IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, the Fc region is incapable of inducing complement activity and / or incapable of inducing antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the Fc region comprises one or more modifications, including, but not limited to, an amino acid substitution. In certain embodiments, the Fc region of a humanized anti-C1q antibody of the present disclosure comprises an amino acid substitution at position 248 according to the Kabat numbering convention or at a position corresponding to position 248 according to the Kabat numbering convention, and / or at position 241 according to the Kabat numbering convention or at a position corresponding to position 241 according to the Kabat numbering convention. In some embodiments, the amino acid substitution at position 248 or a position corresponding to position 248 inhibits the Fc region from interacting with an Fc receptor. In some embodiments, the amino acid substitution at position 248 or a position corresponding to position 248 is a leucine to glutamate amino acid substitution. In some embodiments, the amino acid substitution at position 241 or a position corresponding to position 241 prevents an arm switch in the antibody. In some embodiments, the amino acid substitution at position 241 or a position corresponding to position 241 is a serine to proline amino acid substitution. In certain embodiments, the Fc region of a humanized anti-C1q antibody of the present disclosure comprises an amino acid sequence of SEQ ID NO:47, or an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% homology to the amino acid sequence of SEQ ID NO:47.

[0149] Anti-C1q Fab fragment All anti-C1q antibody Fab fragment sequences are incorporated by reference from US patent application Ser. No. 15 / 360,549, which is incorporated by reference herein for the antibodies and related compositions it discloses.

[0150] In certain embodiments, the present disclosure provides a method for the production of a heavy chain (V H / C H 1) and light chain (V L / C L ), wherein the anti-C1q antibody Fab fragment binds to the C1q protein and comprises six complementarity determining regions (CDRs) (three of which are V L and V H The heavy chain of the antibody Fab fragment is truncated after the first heavy chain domain of IgG1 (SEQ ID NO: 39) and comprises the amino acid sequence:

[0151] TIFF2025503545000015.tif45170

[0152] The complementarity determining regions (CDRs) of SEQ ID NO:39 are shown in bold and underlined text.

[0153] The light chain domain of the antibody Fab fragment comprises the following amino acid sequence (SEQ ID NO:40).

[0154] TIFF2025503545000016.tif39170

[0155] The complementarity determining regions (CDRs) of SEQ ID NO:40 are shown in bold and underlined text.

[0156] Anti-C1q single-arm antibody In certain aspects, the disclosure provides an antibody that binds to a protein in the complement cascade, for example, a C1q protein. The antibody that binds to C1q comprises a single C1q antigen binding arm and an Fc region. The single C1q antigen binding arm may comprise a light chain variable domain and a heavy chain variable domain. The Fc region may comprise a complex of a first and a second Fc polypeptide. The Fc region may comprise an Fcγ receptor binding site mutation. The antibody may be of the IgG4 class. In some embodiments, one of the Fc polypeptides, but not both, is an N-terminal truncated heavy chain. In some embodiments, the Fcγ receptor is FcγRI, FcγRII, or FcγRIII, preferably FcγRI. The Fcγ receptor binding site mutation may comprise an IgG4 L115E mutation.

[0157] TIFF2025503545000017.tif39170

[0158] The complementarity determining regions (CDRs) of SEQ ID NO: 40 are shown in bold and underlined text. In some embodiments, the light chain variable domain HVR-L1 has the sequence RASKSINKYLA (SEQ ID NO: 5), the light chain variable domain HVR-L2 has the sequence SGSTLQS (SEQ ID NO: 6), and the light chain variable domain HVR-L3 has the sequence QQHNEYPLT (SEQ ID NO: 7).

[0159] One heavy chain (heavy chain 1 domain) of the single-arm antibody may comprise the following amino acid sequence (SEQ ID NO:2).

[0160] TIFF2025503545000018.tif66170

[0161] The complementarity determining regions (CDRs) of SEQ ID NO:2 are shown in bold and underlined text. The knob of the whole T366W mutation (corresponding to the IgG4 T246W mutation) of SEQ ID NO:2 is shown in underlined text. The S241P (corresponding to the S108P for IgG4 arm swapping) and L248E (corresponding to the L115E mutation for FCR) mutations are represented in bold. In some embodiments, the HVR-H1 of the heavy chain variable domain has the sequence GYHFTSYWMH (SEQ ID NO:9), the HVR-H2 of the heavy chain variable domain has the sequence VIHPNSGSINYNEKFES (SEQ ID NO:10), and the HVR-H3 of the heavy chain variable domain has the sequence ERDSTEVLPMDY (SEQ ID NO:11).

[0162] The second heavy chain (heavy chain 2 domain) of the N-terminally truncated single-arm antibody may comprise the following amino acid sequence (SEQ ID NO:3).

[0163] TIFF2025503545000019.tif45170

[0164] There is no heavy chain variable domain and CDRs in SEQ ID NO: 3. The knobs for the hole T366S / L368A / Y407V mutations in SEQ ID NO: 3 are shown in underlined text. The S241P and L248E mutations are shown in bold.

[0165] In some embodiments, an antibody that binds C1q is A light chain domain comprising the amino acid sequence of SEQ ID NO: 40; a first heavy chain domain comprising the amino acid sequence of SEQ ID NO:2; and a second heavy chain domain comprising the amino acid sequence of SEQ ID NO:3, wherein the second heavy chain domain is an N-terminal truncated heavy chain.

[0166] C1s inhibitors The inhibitor of the classical complement pathway may be a C1s inhibitor, for example, a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0167] Exemplary C1s small molecule inhibitors are described in US patent application Ser. No. 17 / 379,334, the contents of which are incorporated herein by reference.

[0168] Anti-complement C1s antibody Suitable inhibitors include antibodies that bind to complement C1s protein (i.e., anti-complement C1s antibodies, also referred to herein as anti-C1s antibodies and C1s antibodies) and nucleic acid molecules encoding such antibodies. Complement C1s is an attractive target because it is upstream in the complement cascade and has a narrow range of substrate specificity. Furthermore, it is possible to obtain antibodies (such as, but not limited to, monoclonal antibodies) that specifically bind to the activated form of C1s.

[0169] All sequences referred to in the next two paragraphs are incorporated by reference into US patent application Ser. No. 14 / 890,811, which is incorporated by reference herein for the antibodies and related compositions it discloses.

[0170] In certain aspects, disclosed herein is a method of administering an anti-C1s antibody. The antibody can be a murine antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3, and the heavy chain comprises HVR-H1, HVR-H2, and HVR-H3 of the murine anti-human C1s monoclonal antibody 5A1 produced by the hybridoma cell line deposited with the ATCC on May 15, 2013, or its progeny (ATCC Accession No. PTA-120351). In other embodiments, the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3, and the heavy chain variable domain comprises HVR-H1, HVR-H2, and HVR-H3 of the mouse anti-human C1s monoclonal antibody 5C12 produced by the hybridoma cell line deposited with the ATCC on May 15, 2013, or its progeny (ATCC Accession No. PTA-120352).

[0171] In some embodiments, the antibody specifically binds to C1s or C1s proenzyme and inhibits its biological activity, such as C1s binding to C1q, C1s binding to C1r, or C2 or C4. The biological activity can be the proteolytic enzyme activity of C1s, conversion of the C1s proenzyme to an active protease, or proteolytic cleavage of C2 or C4. In certain embodiments, the biological activity is activation of the classical complement activation pathway, activation of antibodies and complement dependent cytotoxicity, or C1F hemolysis.

[0172] All anti-C1s antibody sequences are incorporated by reference from US Pat. No. 8,877,197, which is incorporated by reference herein for the antibodies and related compositions it discloses.

[0173] In some embodiments, an anti-C1s antibody (e.g., an antibody of interest that specifically binds to an epitope in complement C1s protein) comprises a) a light chain region that comprises CDRs selected from SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, and b) a heavy chain region that comprises CDRs selected from SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20. In some of these embodiments, the anti-C1s antibody comprises humanized VH and / or VL framework regions. SEQ ID NO: 15: SSVSSSYLHWYQ, SEQ ID NO: 16: STSNLASGVP, SEQ ID NO: 17: HQYYRLPPIT, SEQ ID NO:18: GFTFSNYAMSWV, SEQ ID NO: 19: ISSGGSHTYY, SEQ ID NO:20: ARLFTGYAMDY.

[0174] In some embodiments, an anti-C1s antibody of the disclosure comprises a light chain variable region comprising the amino acid sequence SEQ ID NO:21.

[0175] In some embodiments, an anti-C1s antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO:22.

[0176] TIFF2025503545000020.tif61170

[0177] In some embodiments, an anti-C1s antibody of the disclosure comprises a light chain variable region comprising the amino acid sequence SEQ ID NO:23.

[0178] In some embodiments, an anti-C1s antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO:24.

[0179] TIFF2025503545000021.tif61170

[0180] In some embodiments, an anti-C1s antibody of the disclosure comprises a light chain comprising the amino acid sequence SEQ ID NO:25.

[0181] In some embodiments, an anti-C1s antibody of the disclosure comprises a heavy chain comprising the amino acid sequence SEQ ID NO:26.

[0182] The stimulimab antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:25 and a heavy chain comprising the amino acid sequence of SEQ ID NO:26.

[0183] TIFF2025503545000022.tif115170

[0184] In some embodiments, an anti-C1s antibody of the disclosure comprises a) a light chain region comprising CDRs selected from SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 17, and b) a heavy chain region comprising CDRs selected from SEQ ID NO: 29, SEQ ID NO: 30, and SEQ ID NO: 31. In some of these embodiments, the anti-C1s antibody comprises humanized VH and / or VL framework regions. SEQ ID NO:27: TASSSVSSSYLH; SEQ ID NO:28: STSNLAS; SEQ ID NO:17: HQYYRLPPIT; SEQ ID NO:29: NYAMS; SEQ ID NO:30: TISSGGSHTYYLDSVKG; SEQ ID NO:43: LFTGHAMDY.

[0185] In some embodiments, an anti-C1s antibody of the disclosure comprises a light chain variable region comprising the amino acid sequence SEQ ID NO:44.

[0186] In some embodiments, an anti-C1s antibody of the disclosure comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO:45.

[0187] QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYLHWYQQKPGSSPKLWIYSTSNLASGVPARFSGSGSGTFYSLTISSMEAEDDATYYCHQYYRLPPITFGAGTKLELK (SEQ ID NO: 44) EVMLVESGGALVKPGGSLKLSCAASGFTFSNYAMSWVRQIPEKRLEWVATISSGGSHTYYLDSVKGRFTISRDNARDTLYLQMSSLRSEDTALYYCARLFTGYAMDYWGQGTSVTVSS (SEQ ID NO: 45)

[0188] The anti-C1s antibody may be selected from an antigen-binding fragment, an Ig monomer, a Fab fragment, a F(ab')2 fragment, an Fd fragment, an scFv, a scAb, a dAb, an Fv, a single domain heavy chain antibody, a single domain light chain antibody, a monospecific antibody, a bispecific antibody, or a multispecific antibody.

[0189] Disclosed herein are methods of administering an antibody that competes for binding to the epitope bound by antibody IPN003 (also referred to herein as "IPN-M34" or "M34" or "TNT003"), e.g., an antibody that comprises a variable domain of antibody IPN003, such as antibody IPN003.

[0190] C1r inhibitors The inhibitor of the classical complement pathway may be a C1r inhibitor, for example, a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0191] The anti-C1r antibodies disclosed herein are potent inhibitors of C1r.

[0192] The anti-C1r antibodies disclosed herein inhibit the interaction between C1r and C1q, or between C1r and C1s, or the anti-C1r antibodies inhibit the catalytic activity of C1r, or inhibit the processing of pro-C1r into active proteases.

[0193] C1 complex inhibitors The inhibitor of the classical complement pathway may be a C1 inhibitor, for example, a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0194] The anti-C1 complex antibodies disclosed herein are potent inhibitors of the C1 complex.

[0195] The anti-C1 complex antibodies disclosed herein inhibit activation of C1r or C1s or block their ability to act on C2 or C4. The anti-C1 complex antibodies disclosed herein bind to a combination epitope within the C1 complex, which combination epitope includes both C1q and C1s, both C1q and C1r, both C1r and C1s, or amino acids of each of C1q, C1r, and C1s.

[0196] C2 inhibitor The inhibitor of the classical complement pathway may be a C2 inhibitor, for example, a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0197] The anti-C2 inhibitors disclosed herein are potent inhibitors of C2.

[0198] C3 inhibitors The inhibitor of the classical complement pathway may be a C3 inhibitor, such as a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0199] The anti-C3 inhibitors disclosed herein are potent inhibitors of C3. In some embodiments, the C3 inhibitor is APL-9 (Apellis) and / or AMY-101 (Amyndas) and / or IVT CB 2782-PEG (Catalyst Biosciences and Biogen).

[0200] C4 inhibitors The inhibitor of the classical complement pathway may be a C4 inhibitor, such as a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent.

[0201] The anti-C4 inhibitors disclosed herein are potent inhibitors of C4.

[0202] Complement inhibition Many molecules that inhibit the activity of complement are known. In addition to known compounds, suitable inhibitors can be screened by the methods described herein. As mentioned above, normal cells can produce proteins that block complement activity, such as CD59, C1 inhibitor, etc. In some embodiments of the present disclosure, complement is inhibited by upregulating the expression of genes that code for such polypeptides.

[0203] Modifications of molecules that block complement activation are also known in the art. For example, such molecules include modified complement receptors, such as, but not limited to, soluble CR1. The mature protein of the most common allotype of CR1 contains 1998 amino acid residues: an extracellular domain of 1930 residues, a transmembrane region of 25 residues, and a cytoplasmic domain of 43 residues. The entire extracellular domain consists of 30 repeating units, termed short consensus repeats (SCRs) or complement control protein repeats (CCPRs), each consisting of 60-70 amino acid residues. Recent data show that C1q binds specifically to human CR1. Thus, CR1 recognizes all three complement opsonins, namely, C3b, C4b, and C1q. A soluble version of recombinant human CR1 (sCR1), lacking the transmembrane and cytoplasmic domains, has been generated and shown to retain all known functions of native CR1. The cardioprotective role of sCR1 in animal models of ischemia / reperfusion injury has been confirmed. Several types of human C1q receptors (C1qR) have been described. These include a ubiquitously distributed 60-67 kDa receptor termed cC1qR because it binds to the collagen-like domain of C1q. This C1qR variant was shown to be calreticulin; a 126 kDa receptor that regulates monocyte phagocytosis. gC1qR is not a membrane-bound molecule, but rather a secreted soluble protein with affinity for the globular region of C1q and may act as a fluid-phase regulator of complement activation.

[0204] Decay-accelerating factor (DAF) (CD55) consists of four SCRs and a serine / threonine-rich domain that is capable of extensive O-linked glycosylation. DAF is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor and acts by dissociating the C3 and C5 convertases through its ability to bind C4b and C3b. A soluble version of DAF (sDAF) has been shown to inhibit complement activation.

[0205] C1 inhibitor, a member of the "serpin" family of serine protease inhibitors, is a heavily glycosylated plasma protein that prevents fluid-phase C1 activation. C1 inhibitor regulates the classical pathway of complement activation by blocking the active sites of C1r and C1s, dissociating them from C1q.

[0206] Peptide inhibitors of complement activation include C5a, and other inhibitory molecules include fucans.

[0207] Treatment methods The present disclosure presents a model that evaluates complement activation, alone or in combination with NfL and age, which predicts HD stage more accurately than NfL alone or in combination with age. Data from HD clinical trials demonstrate that patients identified by using a model that evaluates high C4a levels and / or high C4a / C4 ratios show clinical improvement with anti-C1q antibody treatment. Clinical trial data also demonstrate that treatment with full-length anti-C1q antibodies provides clinical benefit to HD patients identified by using a model that evaluates complement activation, alone or in combination with NfL and age. Clinical trial data also demonstrate that taking into account complement activation, NfL, and age, and using full-length anti-C1q antibodies provides a robust clinical benefit to HD patients. Clinical benefit was measured by the composite Unified Huntington's Disease Rating Scale (cUHDRS) or by any of the following domains: cognition (SDMT, SWR), total functional capacity (TFC), and total motor capacity (TMS).

[0208] The present disclosure generally relates to a method of treating Huntington's disease in a subject in need thereof, the method including determining whether the subject has an elevated C4a level or an elevated C4a / C4 ratio, and administering to the subject an inhibitor of the classical complement pathway if the subject has an elevated C4a level or an elevated C4a / C4 ratio. A therapeutically effective amount of the inhibitor can be administered.

[0209] Elevated C4a levels may be higher than C4a levels in normal or healthy subjects, such as subjects of similar age. Patients treated with inhibitors of the classical complement pathway (e.g., full-length C1q antibodies) showed improvement from baseline in cUHDRS and / or components of cUHDRS over 6 months of treatment. This improvement was more pronounced in patients with excess complement activity at baseline, with 75% of patients with high CSF4a levels at baseline showing improvement in cUHDRS over 6 months of treatment. This suggests a rapid response to anti-C1q therapy via enhanced synaptic function. C4a is an objective measure that can indicate excess classical complement activity in CSF that correlates with disease stage and multiple clinical endpoints in HD. These results support the possibility of an intensification strategy for patients with high C4a levels and excess complement activity who may benefit from anti-C1q therapy. C4a can signal disease stage beyond that predicted by age (Figure 5). The data below the diagonal in FIG. 5 show that LM2 (age+C4a) has lower error and therefore higher accuracy than LM1 (age alone).

[0210] The elevated C4a level can be higher than the baseline C4a level. For example, the baseline C4a level is equal to or greater than the median C4a level in samples from subjects with Huntington's disease (e.g., subjects of the same age). In other embodiments, the baseline C4a level is equal to or greater than the 75th percentile of C4a levels in samples from normal or healthy subjects (subjects not suffering from Huntington's disease), such as subjects of similar age. Approximately 50% of HD patients have elevated CSF levels of the complement activation product C4a in the natural history cohort (Figures 7A-7B). The median C4a level in samples from Huntington's disease subjects is similar to the 75th percentile of C4a levels in samples from normal or healthy subjects (Figure 7A).

[0211] In some embodiments, the elevated C4a level is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% higher than the baseline C4a level. In some embodiments, the elevated C4a level is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-100%, 100%-200%, 200%-300%, 300%-400%, or 400%-500% higher than the baseline C4a level.

[0212] Patients were divided into two groups based on the C4a / C4 ratio at baseline (Figure 9). Baseline is the median C4a / C4 ratio in samples from Huntington's disease subjects, which is similar to the 75th percentile of C4a / C4 ratios in samples from normal or healthy subjects. High baseline complement patients showed consistent and significant improvement in cUHDRS over the 24-week treatment period (Figure 10).

[0213] Thus, the elevated C4a / C4 ratio may be greater than the C4a / C4 ratio of a normal or healthy subject, such as a subject of similar age. In some embodiments, the elevated C4a / C4 ratio is greater than a reference C4a / C4 ratio. The reference C4a / C4 ratio may be equal to or greater than the median C4a / C4 ratio in samples from subjects with Huntington's disease, such as subjects of similar age. In other embodiments, the reference C4a / C4 ratio is equal to or greater than the 75th percentile C4a / C4 ratio in samples from normal or healthy subjects (subjects not suffering from Huntington's disease), such as subjects of similar age.

[0214] In some embodiments, the elevated C4a / C4 ratio is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the baseline C4a / C4 ratio. In some embodiments, the elevated C4a / C4 ratio is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-100%, 100%-200%, 200%-300%, 300%-400%, or 400%-500% greater than the baseline C4a / C4 ratio.

[0215] In some embodiments, the level of C4a or the C4a / C4 ratio is measured in cerebrospinal fluid (CSF) or plasma. Any method of measuring complement C4a and C4 levels can be used and is well known to those skilled in the art, including but not limited to commercially available ELISA kits such as those from Quidel and SVAR.

[0216] Neurofilament light chain (NfL) is a powerful monitoring and prognostic biomarker for HD. However, a model combining complement activation, NfL, and age more accurately predicts HD stage than NfL alone (Figures 6A-6B).

[0217] In some embodiments, the subject has an elevated level of neurofilament light chain (NfL). The elevated NfL level can be higher than the NfL level of a normal or healthy subject, such as a subject of similar age. In some embodiments, the elevated NfL level is higher than a baseline NfL level. The baseline NfL level is about 100pg / ml, 200pg / ml, 300pg / ml, 400pg / ml, 500pg / ml, 600pg / ml, 700pg / ml, 800pg / ml, 900pg / ml, 1000pg / ml, 1100pg / ml, 1200pg / ml, 1300pg / ml, 1400pg / ml, 1500pg / ml, 1600pg / ml, 1700pg / ml, 1800pg / ml, 1900pg / ml, or 2000pg / ml. In some embodiments, the elevated NfL level is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% higher than the NfL level of a normal or healthy subject or a reference NfL level. , 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1500%, 2000%, 2500%, 3000%, 3500%, 4000%, 4500%, or 5000% higher. In some embodiments, the elevated NfL level is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-10 ...30%-30%, 40%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 50%-30%, 50%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-90%, 10%-20% 0%-200%, 200%-300%, 300%-400%, 400%-500%, 500%-600%, 600%-700%, 700%-800%, 800%-900%, 900%-1000%, 1000%-2000%, 2000%-3000%, 3000%-4000%, or 4000%-5000% higher. In some embodiments, the level of NfL is measured in cerebrospinal fluid (CSF).

[0218] In other embodiments, the level of NfL is measured in plasma. Baseline NfL levels are about 1 pg / ml, 2 pg / ml, 3 pg / ml, 4 pg / ml, 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, 19 pg / ml, or 20 pg / ml. In some embodiments, the elevated NfL level is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% higher than the NfL level of a normal or healthy subject or a reference NfL level. , 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1500%, 2000%, 2500%, 3000%, 3500%, 4000%, 4500%, or 5000% higher. In some embodiments, the elevated NfL level is at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-10 ...30%-30%, 40%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 50%-30%, 50%-40%, 50%-50%, 60%-60%, 70%-80%, 80%-90%, 90%-100%, 10%-20%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-20%, 10%-30%, 10%-40%, 10%-50%, 10%-50%, 10%-60%, 10%-70%, 10%-80%, 10%-90%, 10%-20% 0%-200%, 200%-300%, 300%-400%, 400%-500%, 500%-600%, 600%-700%, 700%-800%, 800%-900%, 900%-1000%, 1000%-2000%, 2000%-3000%, 3000%-4000%, or 4000%-5000% higher.

[0219] In some embodiments, the inhibitor of the classical complement pathway is a C1q inhibitor, e.g., a small molecule, an antibody, an aptamer, an antisense nucleic acid, or a gene editing agent. The antibody can be a C1q antibody described herein. For example, the antibody can include a heavy chain and a light chain, wherein the heavy chain includes the amino acid sequence of SEQ ID NO: 14, and the light chain includes the amino acid sequence of SEQ ID NO: 40. Any suitable administration can be used in the methods described herein. For example, the antibody may be administered at a dose of at least 5 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 45 mg / kg, at least 50 mg / kg, at least 55 mg / kg, at least 60 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, or at least 100 mg / kg. In some embodiments, the antibody is administered at a dose of 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 105 mg / kg, 110 mg / kg 120 mg / kg, 130 mg / kg, 140 mg / kg, or 150 mg / kg. In some embodiments, the antibody is administered at a dose of 75 mg / kg on days 1 and 5 or 6. In some embodiments, the antibody is further administered at a dose of 100 mg / kg every two weeks.

[0220] In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered weekly, biweekly, monthly, 6 weeks, or bimonthly. In some embodiments, the antibody is administered for at least 3 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. In some embodiments, the antibody is administered for 3 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0221] In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 14 and the light chain comprises the amino acid sequence of SEQ ID NO: 40. The antibody may be administered at a dose of 75 mg / kg on days 1 and 5 or 6. In some embodiments, the antibody is further administered at a dose of 100 mg / kg every two weeks. EXAMPLES

[0222] Example 1: Improved HD stage prediction model Discovery and tested cohorts were patients from University College London (UCL) (n=60) and HDClarity (n=100), respectively. Complement proteins and NfL were measured using in-house ELISA and Uman kits, respectively. A machine learning model was developed to assess the contribution of complement activation to cUHDRS. The accuracy and improvement of this model over a linear model of NfL and age was determined by root mean square error.

[0223] C4 was measured by sandwich ELISA. Plates were coated with 3ug / ml of polyclonal raised to C4 (goat anti-human C4, Complement Tech, A205). CSF was diluted 1:5000 in dPBS (Delbecco's PBS) buffer containing 10mM EDTA and incubated overnight at 4°C. Plates were washed and incubated with antibody anti-C4 antibody conjugated to alkaline phosphatase (Abcam ab47788) (1:2000 dilution). Plates were washed 3 times with wash buffer and developed using 75μL of alkaline phosphatase substrate (Life Technologies, T2214). After 20 minutes at room temperature, plates were read using a luminometer. Standards were fitted using 4PL logistic fit to determine unknown concentrations. Analyte levels were corrected for dilution and then plotted using GraphPad Prism.

[0224] C4a was measured in a competitive-based ELISA. Plates were coated with 10ug / ml CT-C4a (rabbit anti-human C4a, Complement Tech A206), a polyclonal antiserum raised to C4a. CSF was diluted 1:10 in buffer dPBS containing 10mM EDTA and 10ng / ml biotinylated C4a and incubated overnight at 4°C. Plates were washed three times and incubated with Avidin-AP (1:1000 dilution). Alkaline phosphatase activity was detected as described above.

[0225] Patients experienced improved clinical outcomes as measured by the Composite UHDRS (cUHDRS), a clinical rating scale used to assess four domains of clinical performance and capacity in HD, including motor function, cognitive function, behavioral abnormalities, and functional ability. The cUHDRS is the primary endpoint in HD, consisting of four subdomains (cognitive, motor, and functional) that assess HD disease progression.

[0226] Overall, patients maintained clinical function with no decline from baseline in cUHDRS over 6 months of treatment (n=23), compared to natural history data showing that HD patients experience a decline of approximately 1.2 points over 1 year, or 0.6 points over 6 months. Additionally, 56% of patients showed improvement from baseline in cUHDRS and all subdomains of cUHDRS over 6 months of treatment. This improvement was more pronounced in patients with excess complement activity at baseline, with 75% of patients with high CSFC4a levels at baseline showing improvement in cUHDRS over 6 months of treatment. This suggests a rapid response to anti-C1q therapy via enhanced synaptic function. C4a is an objective measure of excess classical complement activity in the CSF and correlates with disease stage and multiple clinical endpoints in HD. These results support the possibility of an intensification strategy for patients with high C4a levels and excess complement activity who may benefit from anti-C1q therapy.

[0227] Excess classical complement activity in the CSF (C4a) of HD patients is associated with impaired function and disease severity (Figure 2). Moreover, CSF C4a correlates with individual domains of the cUHDRS (Table 1). [Table 3]

[0228] C4a is increased in the CSF of patients with manifest HD (Figure 3). NFL is significantly elevated in the CSF of patients with manifest HD, and CSF NFL correlates with CSF C4a (Figures 4A-4B).

[0229] Using the HDClarity dataset, we built several machine learning models to determine whether complement factors could help understand the clinical assessment of patients in manifest HD at the time of increasing NfL plateau. Consistent with previous reports, we found that NfL and age were informative in predicting the clinical severity score of patients. In addition, the models suggested that proteins involved in the activation of the classical complement pathway, C4a and C4, were the next important biomarkers for predicting both cUHDRS as well as individual clinical trials. These results confirm the high importance of the complement pathway in HD progression and suggest that these proteins may have value in modeling and predicting disease stage and treatment efficacy. Furthermore, these models can serve as a quantitative and sensitive tool to evaluate treatment efficacy in short-term studies when changes in traditional functional assessments are difficult to accurately determine.

[0230] C4a can signal disease stage beyond that predicted from age (Figure 5). To determine whether C4a provides additional information on disease stage beyond age alone, we assessed the statistical significance of the C4a coefficient towards predicting HD disease stage. Two linear regression models were used to compare the correlation between age and age+C4a and HD category. LM2, which includes C4a in addition to age, more accurately predicts HD disease stage compared to LM1. The diagonal line represents equal accuracy between the two models. Data below the diagonal line show that LM2 has lower error and therefore higher accuracy than LM1 (Figure 5). The contribution of C4a is statistically significant (p=0.007), indicating that C4a levels in HD patients are indicative of their disease stage beyond what would be expected as an age effect.

[0231] We show that a model combining complement activation, NfL, and age more accurately predicts HD stage than NfL alone (Figures 6A-6B).

[0232] Approximately 50% of HD patients have elevated CSF levels of the complement activation product C4a in the natural history cohort; similar range in the current study - these patients may respond better to anti-C1q therapy (Figures 7A-7B).

[0233] CSF C4a / C4 ratio: represents a sensitive measure of ongoing complement activation. C1q activation activity reduces (consumes) C4. C1q activation increases (produces) C4a. The C4a / C4 ratio corrects for genetic variability between subjects (Figure 8).

[0234] Example 2: A Phase 2a Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Full-Length C1q Antibody in Subjects with or at Risk for Manifest Huntington's Disease overview Subjects received induction doses of 75 mg / kg full length C1q antibody (the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain comprising the amino acid sequence of SEQ ID NO: 40) by intravenous (IV) infusion on days 1 and 5 or 6, followed by maintenance doses of 100 mg / kg every 2 weeks (weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22) with follow-up at weeks 24, 28, and 36. All full length C1q antibody infusions were administered at clinic visits.

[0235] All subjects were contacted 6 months after study completion to collect information focusing on clinical signs and symptoms suggestive of autoimmunity, e.g., fatigue, muscle pain, swelling, redness, low-grade fever, difficulty concentrating, numbness and tingling, hair loss, or skin rash.

[0236] Blood samples for PK / PD assessments were collected serially after the first and last doses. Predose samples were collected at all dosing visits (days 1, 5 / 6, and weeks 2 through 22) before starting the full-length C1q antibody infusion. After the end of the infusion, blood samples were collected at days 5 / 6, weeks 2, 6, 10, 14, and 18. PK / PD samples were also collected at the week 24, 28, and 36 visits.

[0237] Cerebrospinal fluid (CSF) sampling for PK and PD assessments was performed at screening, 6 and 12 weeks pre-dose, and 24 and 36 weeks post-dose.

[0238] EEG was performed during screening and pre-dose on day 1, week 6, week 12, week 18, and weeks 24 and 36.

[0239] In the Phase 2 study, safety was evaluated in all 28 patients enrolled. Initial target engagement data included pharmacokinetics (PK) and pharmacodynamics (PD) in 17 patients who completed the 24-week treatment period. Initial efficacy and biomarker data included clinical outcomes measured by the Unified Huntington's Disease Rating Scale (UHDRS) in all 23 patients who completed the 24-week treatment period, as well as neurofilament light chain (NfL) levels in 16 patients who completed the 24-week treatment period. C4a, C4, and Nfl levels were measured as described in Example 1. Initial findings indicate that treatment with full-length C1q antibody was generally well tolerated, with robust target engagement of C1q in both serum and cerebrospinal fluid (CSF) throughout the dosing period. Notably, significant improvements in UHDRS were observed, while NfL levels in both plasma and CSF remained generally unchanged and consistent with the natural history of HD.

[0240] Initial data with full-length C1q antibodies suggest that protection of functioning synapses via C1q inhibition may lead to rapid functional improvement in HD and potentially other neurodegenerative diseases. The clinical response signals observed especially in patients with elevated C4a also suggest that patients with excess complement activity may respond better and more rapidly to anti-C1q therapy.

[0241] Phase 2a data was analyzed using CSF C4a / C4 ratio as a measure of ongoing complement activity (Figure 9). Patients were divided into two groups based on C4a / C4 levels at baseline. High baseline complement patients showed consistent and significant improvement in cUHDRS over the 24-week treatment period (Figure 10). Biomarker differentiation responses are unlikely to be placebo driven. Patients with high baseline C4a / C4 ratios also improved from baseline in cUHDRS over the 24-week treatment period compared to natural history. The decline in the low complement activity cohort is consistent with natural history. Additionally, patients with high baseline C4a / C4 ratios consistently improved in cUHDRS subdomains over the 24-week treatment period (Figures 11A-11D). 75% of patients with high baseline complement activity (C4a / C4) improved in cUHDRS at week 24 compared to 36% with low activation (Figures 12A-12B).

[0242] Plasma NfL levels are consistent with HD natural history at 24 weeks (Figure 13). CSF NfL levels are also consistent with HD natural history at 24 weeks (Figure 14). HD natural history data are for the Manifest cohort (Rodriguez, et al., Sci Transl Med. 2020 12 16;12(574)) and (Tabrizi, NEJM 2019,38:2307). Synaptic loss impacts neuronal function and precedes neuronal loss and NfL release (Ravalia, 2021; Milnerwood and Raymond, 2010; Milnerwood et al., 2010; Parsons and Raymond, 2014; Ravalia et al., 2021; Alirezaei1 et al., 2020 Mol Neurobiol. 57:469-491).

[0243] The combination of baseline C4a ratio, NfL and age identifies distinct groups of differential cUHDRS at week 24 (Figures 15A-15B). Improvers identified by the model tend to have higher baseline C4a / C4, lower baseline NfL, and be slightly younger.

[0244] Example 3: A Phase 2a Open-Label Study Evaluating the Efficacy of Intravenous Full-Length C1q Antibody in Subjects with or at Risk for Manifest Huntington's Disease overview Subjects received induction doses of 75 mg / kg full length C1q antibody (the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain comprising the amino acid sequence of SEQ ID NO: 40) by intravenous (IV) infusion on days 1 and 5 or 6, followed by maintenance doses of 100 mg / kg every 2 weeks (weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22) with follow-up at weeks 24, 28, and 36. All full length C1q antibody infusions were administered at clinic visits.

[0245] Blood samples for PK / PD assessments were collected serially after the first and last doses. Predose samples were collected at all dosing visits (day 1, day 5 / 6, week 2 or week 22) before starting the full-length C1q antibody infusion. After the end of the infusion, blood samples were collected at days 5 / 6, week 2, week 6, week 10, week 14, and week 18. PK / PD samples were also collected at the week 24, week 28, and week 36 visits.

[0246] Cerebrospinal fluid (CSF) sampling for PK and PD assessments was performed at screening, 6 and 12 weeks pre-dose, and 24 and 36 weeks post-dose.

[0247] EEG was performed during screening and pre-dose on day 1, week 6, week 12, week 18, and weeks 24 and 36.

[0248] Initial data suggests that full length C1q antibodies demonstrated rapid, robust and long-lasting complement engagement. Full C1q engagement was assessed in the CSF at the first time point. Figure 16A shows full length C1q antibody levels in the CSF and Figure 16B shows full C1q engagement in the CSF. Full C1q engagement was assessed in serum at the first dose and 6-10 weeks after full length C1q antibody treatment was discontinued. Figure 17A shows full length C1q antibody levels in serum and Figure 17B shows full C1q engagement in serum.

[0249] The data also show prolonged target engagement and downstream complement inhibition within the CNS 14 weeks after the last dose. Figure 18 shows the effect of full-length C1q antibody persisting through a 3-month treatment hiatus. C4a release is a pharmacodynamic marker of C1q target engagement. All patients have evidence of continued target engagement 3 months after the last dose. This is consistent with preclinical data showing full-length C1q antibody accumulation at sites of high C1q expression in the CNS.

[0250] Full-length C1q antibody treatment resulted in early and sustained improvements in patients with excessive baseline complement activity. Figures 19A-19B show significant improvements over the treatment period in subjects with excessive vs. low baseline complement activity. Figures 20A-20D show that benefits in patients with high complement activity were demonstrated across most cUHDRS component domains. Figure 20A shows Total Functional Capacity (TFC, activities of daily living). Figure 20B shows Symbol Digit Modalities Test (SDMT, cognition). Figure 20C shows Total Motor Score (TMS). Figure 20D shows Stroop Word Reading Test (SWR, cognition).

[0251] Plasma NfL levels were stable throughout the study. Figure 21 shows that plasma NfL levels are consistent with HD natural history at week 36 with a 4% change from screening (Rodriguez, et al., Sci Transl Med. 2020 12 16;12(574)) and (Tabrizi, NEJM 2019,38:2307). Figure 14 shows that CSF NfL levels are consistent with HD natural history at week 36 with a 16% change from screening. *Results are independent of baseline complement activity.

[0252] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0253] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. A composition for treating Huntington's disease in a subject in need thereof, comprising an inhibitor of the classical complement pathway, wherein the subject has elevated C4a levels or an elevated C4a / C4 ratio.

2. The elevated C4a levels (a) C4a levels in normal or healthy subjects; (b) C4a levels in normal or healthy subjects of similar age, or (c) baseline C4a level and optionally, said baseline C4a level is greater than (i) the median C4a level in samples from Huntington's disease subjects; (ii) the median C4a levels in samples from Huntington's disease subjects of similar age; (iii) the 75th percentile of C4a levels in samples from normal or healthy subjects; or (iv) the 75th percentile of C4a levels in samples from normal or healthy subjects of similar age 2. The composition of claim 1, wherein said normal or healthy subject does not have Huntington's disease.

3. The elevated C4a level is higher than the C4a level in the normal or healthy subject or the baseline C4a level. (a) at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, or 500% higher; or (b) at least 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, 90% to 100%, 100% to 200%, 200% to 300%, 300% to 400%, or 400% to 500% higher; The composition of claim 2.

4. The elevated C4a / C4 ratio (a) C4a / C4 ratio in normal or healthy subjects; (b) the C4a / C4 ratio in normal or healthy subjects of similar age, or (c) Standard C4a / C4 ratio and optionally, the reference C4a / C4 ratio is greater than (i) the median C4a / C4 ratio in samples from Huntington's disease subjects; (ii) the median C4a / C4 ratio in samples from Huntington's disease subjects of similar age; (iii) the 75th percentile of the C4a / C4 ratio in samples from normal or healthy subjects; or (iv) the 75th percentile of the C4a / C4 ratio in samples from normal or healthy subjects of similar age 2. The composition of claim 1, wherein said normal or healthy subject does not have Huntington's disease.

5. The elevated C4a / C4 ratio is higher than the C4a / C4 ratio in the normal or healthy subject or the reference C4a / C4 ratio. (a) at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, or 500% greater; or (b) at least 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, 90% to 100%, 100% to 200%, 200% to 300%, 300% to 400%, or 400% to 500% greater; The composition of claim 4.

6. The composition of claim 1 , wherein the C4a level or the C4a / C4 ratio is measured in cerebrospinal fluid (CSF) or plasma.

7. 10. The composition of claim 1, wherein the subject has elevated neurofilament light chain (NfL) levels.

8. The elevated NfL levels are (a) NfL levels in normal or healthy subjects; (b) NfL levels in normal or healthy subjects of similar age, or (c) Reference NfL level and optionally said elevated NfL level is higher than the NfL level of said normal or healthy subject or said reference NfL level. (i) at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 2000%, 3000%, 4000%, or 5000% higher; or (ii) at least 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, 90% to 100%, 100% to 200%, 200% to 300%, 300% to 400%, 400% to 500%, 500% to 600%, 600% to 700%, 700% to 800%, 800% to 900%, 900% to 1000%, 1000% to 2000%, 2000% to 3000%, 3000% to 4000%, or 4000 to 5000% higher; The composition of claim 7.

9. 9. The composition of claim 8, wherein the NfL level is measured in cerebrospinal fluid (CSF), and optionally the baseline NfL level is about 100 pg / ml, 200 pg / ml, 300 pg / ml, 400 pg / ml, 500 pg / ml, 600 pg / ml, 700 pg / ml, 800 pg / ml, 900 pg / ml, 1000 pg / ml, 1100 pg / ml, 1200 pg / ml, 1300 pg / ml, 1400 pg / ml, 1500 pg / ml, 1600 pg / ml, 1700 pg / ml, 1800 pg / ml, 1900 pg / ml, or 2000 pg / ml.

10. 9. The composition of claim 8, wherein the NfL level is measured in plasma, and optionally the reference NfL level is about 1 pg / ml, 2 pg / ml, 3 pg / ml, 4 pg / ml, 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, 19 pg / ml, or 20 pg / ml.

11. 11. The composition of any one of claims 1 to 10, wherein the inhibitor of the classical complement pathway is a C1q inhibitor, a C1r inhibitor, a C1s inhibitor, a C2 inhibitor, a C3 inhibitor, or a C4 inhibitor.

12. The composition of claim 11 , wherein the C1q inhibitor is an anti-C1q antibody.

13. The composition comprising: (a) an antibody dose of at least 75 mg / kg; (b) an antibody dose of 75 mg / kg; (c) an antibody dose of 100 mg / kg; or (d) antibody dose of 75 mg / kg on days 1 and 5 or 6 The composition of claim 12, wherein the composition is administered in a dose of 100 mg / kg or less.

14. 14. The composition of claim 13, wherein the composition is further administered at an antibody dose of 100 mg / kg every two weeks.

15. 14. The composition of claim 13, wherein the composition is administered intravenously, and optionally the composition is further administered once a week, once every two weeks, once a month, once every six weeks, or once every two months.

16. 16. The composition of claim 15, wherein the composition is administered for at least 3 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

17. 13. The composition of claim 12, wherein the antibody is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, an antibody fragment, or an antibody derivative thereof, and optionally the antibody fragment is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, an Fv fragment, a diabody, a single-chain antibody molecule, or a single-arm antibody molecule.

18. The composition of claim 12, wherein the antibody comprises a light chain variable domain comprising HVR-L1 having the amino acid sequence of SEQ ID NO: 5, HVR-L2 having the amino acid sequence of SEQ ID NO: 6, and HVR-L3 having the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable domain comprising HVR-H1 having the amino acid sequence of SEQ ID NO: 9, HVR-H2 having the amino acid sequence of SEQ ID NO: 10, and HVR-H3 having the amino acid sequence of SEQ ID NO:

11.

19. 19. The composition of claim 18, wherein the antibody comprises a light chain variable domain comprising an amino acid sequence having at least about 95% identity to an amino acid sequence selected from SEQ ID NOs: 4 and 35-38, and a heavy chain variable domain comprising an amino acid sequence having at least about 95% identity to an amino acid sequence selected from SEQ ID NOs: 8 and 31-34.

20. 19. The composition of claim 18, wherein the light chain variable domain comprises an amino acid sequence selected from SEQ ID NOs: 4 and 35-38, and the heavy chain variable domain comprises an amino acid sequence selected from SEQ ID NOs: 8 and 31-34.

21. 19. The composition of claim 18, wherein the antibody fragment comprises a heavy chain Fab fragment of SEQ ID NO: 39 and a light chain Fab fragment of SEQ ID NO:

40.

22. A composition for treating Huntington's disease in a subject in need thereof, comprising an antibody, wherein the subject has elevated C4a levels or an elevated C4a / C4 ratio, and the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:

33.

23. 23. The composition of claim 22, wherein the composition is administered intravenously at an antibody dose of at least 75 mg / Kg on days 1 and 5 or 6.

24. 24. The composition of claim 23, wherein the composition is further administered intravenously at an antibody dose of 100 mg / Kg every two weeks.

25. The composition of any one of claims 22 to 24, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain comprising the amino acid sequence of SEQ ID NO:

40.

26. Use of an inhibitor of the classical complement pathway in the manufacture of a medicament for treating Huntington's disease in a subject in need thereof, wherein the subject has elevated C4a levels or an elevated C4a / C4 ratio.

27. ​​Use of an antibody in the manufacture of a medicament for treating Huntington's disease in a subject in need thereof, wherein the subject has elevated C4a levels or an elevated C4a / C4 ratio, and the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 37 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 33.

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