Treatment methods for thoracolumbar vertebral malformations in humans with chondrodysplasia

Abstract

The present invention relates to a method for treating spinal malformations, such as thoracolumbar malformations, in subjects requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor or an NPR-B agonist and / or an NPR-C agonist to the subject.

Description

[Technical Field]

[0001] The present invention provides a method for treating spinal malformations, such as thoracolumbar malformations, in subjects requiring treatment, the method comprising the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor or an NPR-B agonist and / or an NPR-C agonist to the subject. The present invention further provides a method for improving muscle function in subjects requiring improvement of muscle function, particularly a method for therapeutic use in conditions associated with muscle weakness, muscle condition, and / or muscle pain. The methods and uses of the present invention are useful, for example, in the treatment of chondrodysplasia. [Background technology]

[0002] Achondodysplasia is the most common form of non-lethal skeletal malformation, affecting over 250,000 people worldwide. It is caused by a pathogenic variant in the gene encoding fibroblast growth factor receptor 3 (FGFR3) and is transmitted in an autosomal dominant form. FGFR3 is a negative regulator of long bone growth and is highly expressed in chondrocytes of the growth plate.

[0003] Infants with achondroplasia typically have low muscle tone (hypotonia), resulting in delayed motor skill development and weak skeletal muscles, and exacerbating spinal malformations such as kyphosis (Takken et al., Journal of Pediatrics 2017, Vol 150, pp26-30; Patient Guide to Achondroplasia, John Hopkins Dept. Orthapaedic Surgery, 2003). Muscle weakness is also a characteristic feature of achondroplasia in adults (Sims et al., J Appl Physiol (1985) 2018 Mar 1;124(3):696-703; de Vries Am J Med Genet. 2021;185A:1023-1032).

[0004] Spinal malformations in humans with achondroplasia require treatment during infancy, childhood, and adulthood. Infants may require braces or casts, and corrective surgery may be necessary during childhood. In adulthood, kyphosis can progress to spinal stenosis, and surgery is often required to straighten the spine and allow the vertebrae to grow together.

[0005] Thoracolumbar malformations in patients with achondroplasia (ACH) are a significant problem that can lead to severe disability, pain, and discomfort (see, e.g., Misra et al., Neurosurg Focus 14 (1):Article 4, 2003). Thoracolumbar kyphosis (TLK) is one of the most common skeletal manifestations in patients with achondroplasia, causing low back pain, neurological complications, and urinary dysfunction, and may require surgical correction (see, e.g., Tanaka et al., Medicina 2022, 58, 605).

[0006] TLK is prevalent in children with achondroplasia, and is associated with developmental delay, hypotonia, and changes in body shape. In most children with achondroplasia, thoracolumbar kyphosis improves when standing, but if it persists, it is accompanied by significant pain and may lead to surgical intervention later in life (Margalitet et al., J Pediatr Orthop. 2018 Nov / Dec;38(10):491-497). TLK is most common in young children with achondroplasia, and thoracolumbar kyphosis decreases with age, which is associated with increased lumbar lordosis and an increased risk of spinal stenosis in adults (Abousamra 2019 Spine Deform. 2019 Jan;7(1):163-170).

[0007] Thoracolumbar kyphosis is often present at birth or observed within the first six months in 95% of newborns with thoracolumbar kyphosis (ACH) (Kopits 1988, Basic Life Sci. 1988;48:189-97). In these newborns, the TLK ranges from 15 to 25°, with the peak between T12 and L2, and the vertebral structure is normal. After infants begin to sit up, the curve increases significantly (typically over 60° compared to about 5° in healthy children), thought to be a result of developmental delay, hypotonia, and biomechanical changes due to increased skull size, shallower rib cage, and increased abdomen. As children begin to stand, the TLK decreases in the majority of children with ACH, as the biomechanics of the spine and vertebral ossification improve, preventing the malformation from becoming "fixed." The incidence decreases in older children, reaching 11% by age 10. Subsequently, the prevalence exceeds 30% in patients over 30 years of age.

[0008] Thoracolumbar kyphosis typically develops or worsens during infancy when a child begins to sit up, and the condition follows a predictable course over time until the child learns to walk. Kyphosis often begins as a result of physiological anterior compression of the vertebral growth zone, and is frequently associated with Gibbs malformation, vertebral hypoplasia, or apical wedge formation of the vertebral body (typically anterior wedge formation).

[0009] While postural kyphosis spontaneously resolves in the majority of children up to 3 years of age, approximately 30% of children with chondrodysplasia experience persistent kyphosis (TLK angle of approximately 20° or greater), and the apical vertebral bodies (typically L1 or L2) become wedge-shaped. These "gibbus" malformations are associated with an increased incidence and severity of symptomatic spinal stenosis, leading to a higher frequency of surgical intervention later in life (Margalit 2018, J Pediatr Orthop. 2018 Nov / Dec;38(10):491-497 & Kopits 1988). In a cohort of ACH patients, TLK has been reported to be significantly correlated with pain as assessed by the Visual Analogue Scale (VAS) pain score (r=0.433, p=0.021) (Hong 2011, Spine (Phila Pa 1976). 2011 Aug 15;36(18):E1233-9). Margalit 2018 reported that in achondroplasia, apical vertebral displacement, the percentage of apical vertebral wedge formation relative to vertebral height, and developmental delay are associated with unresolved TLK.

[0010] Therefore, if TLK is left uncorrected, it can lead to progressive, fixed thoracolumbar kyphosis and the formation of fixed thoracolumbar kyphosis malformations. In adults with chondrodysplasia, kyphosis malformations are further exacerbated by spinal stenosis and age-related degenerative hypertrophic changes in the ligaments and facet joints of the spine, leading to neurological complications and pain. The incidence of thoracolumbar kyphosis is closely associated with the development of neurological symptoms and injuries (Misra et al., Neurosurg Focus 14 (1):Article 4, 2003).

[0011] Therefore, early treatment or prevention of thoracolumbar kyphosis in infants and young children with chondrodysplasia is important in preventing the development of fixed spinal malformations that can lead to physical deformities, neurological damage, and chronic pain later in life. Consequently, untreated childhood thoracolumbar kyphosis may exacerbate thoracolumbar spinal stenosis syndrome in adults with chondrodysplasia, potentially leading to compression of the spinal cord or cauda equina.

[0012] Therefore, it is important to monitor infants and children with achondroplasia for spinal malformations, such as thoracolumbar kyphosis, and to initiate therapeutic intervention. The C-shape of the spine in children in a seated position is best observed on a lateral plain radiograph. Typically, routine standing lateral and AP radiographs should be taken at 6-month intervals to assess the degree of thoracolumbar kyphosis until the child reaches, for example, 3 years of age. Surgical intervention is indicated if the kyphosis progresses to 30° or more (e.g., T10-L2, T11-L2, or T12-L2 kyphosis angles) during the observation period, if a cuneiform process appears anterior to the vertebra, or if the vertebrae are offset.

[0013] Early treatment or prevention of thoracolumbar kyphosis may involve the use of spinal braces, such as thoracolumbar sacral braces (TLSOs), which can reduce or prevent further progression of thoracolumbar kyphosis. In older children and adults, thoracolumbar surgery, such as anterior and posterior fixation with posterior fixation of the kyphotic portion, may be necessary.

[0014] As reported in the examples herein, in a Phase 2 clinical trial and an open-label extension study, the inventors found that administration of a therapeutically effective dose of an NPR-B agonist, such as nabepeglitide (compound (1)), to children with achondroplasia resulted in a reduction in the thoracolumbar kyphosis angle (Cobb angle) and a statistically significant reduction in thoracolumbar kyphosis as measured by the ACH Z score and the healthy control Z score. The reduction in thoracolumbar kyphosis was associated with a slight increase in lumbar lordosis, which was consistent with a reduction in thoracolumbar kyphosis (e.g., the T11-L2 kyphosis angle).

[0015] Thoracolumbar kyphosis is associated with a spinal / vertebral malformation that can be most advantageously corrected while the epiphyses are open, and as such, the methods and uses of the present invention are advantageous in pediatric chondrodysplasia patients, including pediatric patients with unfixed or fixed thoracolumbar kyphosis. As an example, the methods of the present invention can be used to correct or prevent or reduce the occurrence of spinal vertebral malformations, such as thoracolumbar kyphosis.

[0016] As disclosed herein, thoracolumbar kyphosis may be further accompanied by muscle weakness and hypotonia, and the present invention can be used in patients with chondrodysplasia with closed apophysitis and in adult patients with chondrodysplasia. Inhibition of FGFR3 signaling has attracted attention in the development of therapeutic interventions for the treatment of chondrodysplasia. FGFR3 inhibitors may act on the receptor itself or on downstream signaling pathways to inhibit FGFR3 signaling. Accordingly, suitable examples of FGFR3 inhibitors include tyrosine kinase inhibitors (e.g., infiglatinib, pemigatinib, futovatinib, erdafitinib, or TYRA-300), type C natriuretic peptide (CNP), FGFR3 siRNA, and FGFR3 antisense oligonucleotides.

[0017] Infigratinib is an FGFR-selective tyrosine kinase inhibitor approved for the treatment of certain cancers (Truseltiq), but is currently in clinical development to increase height in children with achondroplasia (Savarirayan et al., Ther Adv Musculoskelet Dis 2022 Mar 21;14).

[0018] TYRA-300 is an orally potent FGFR3-selective tyrosine kinase inhibitor that is active in the presence of mutations, including the FGFR3 V555 mutation, and exhibits selectivity for FGFR3 compared to FGF1 and other FGFR isoforms. TYRA-300 was developed by Tyra Biosciences.

[0019] FGFR3 transmits signals via several intracellular pathways, including signaling factors and activators of transcription (STAT) and mitogen-activated protein kinases (MAPK), and constitutive activation of FGFR3 is associated with the chondrodysplasia phenotype. FGFR3 activation is associated with increased phosphorylation of the STAT and MAPK pathways. The MAPK pathway can be regulated by type C natriuretic peptide (CNP). Binding of CNP to its receptor, natriuretic peptide receptor B (NPR-B), results in cGMP production, activating various signaling mediators, including cyclic nucleotide phosphodiesterases (PDEs), cGMP-regulated ion channels (cGICs), and cGMP-dependent protein kinases (cGKIs and cGKIIs). The CNP / NPR-B effect on FGFR3 is mediated by the activation of RAF-1, and consequently, the activation of cGKII, which inhibits the activation of MEK1 / 2 and ERK1 / 2 in the MAPK pathway. Examples of FGFR3 inhibitors that act downstream of FGFR3 include molecules that activate the NPR-B receptor, which inhibits downstream FGFR3 signaling by inhibiting the mitogen-activated protein kinase (MAPK) pathway.

[0020] Bosolitide is a type C natriuretic peptide (CNP) variant approved for the treatment of chondrodysplasia in pediatric patients whose bones are still growing. It acts directly on the bone growth plate to promote new bone growth.

[0021] TransCon® CNP is a long-acting CNP prodrug currently in clinical development for the treatment of chondrodysplasia in pediatric patients with open epiphysis (Breinholt et al., Br J Clin Pharmacol. 2022 Nov;88(11):4763-4772). In a Phase 2 clinical trial (ACcomplisH), TransCon® CNP demonstrated superiority over placebo in annualized ACH-specific height SDS change and was reported to reduce chondrodysplasia-related adverse events.

[0022] CNP is a potent regulator of growth plate chondrogenesis. Binding of CNP to natriuretic peptide-binding receptor-2 (NPR-B) on the surface of chondrocytes induces intracellular synthesis of cyclic guanosine monophosphate (cGMP) and activates cGMP-dependent signaling (Potter et al., Handb Exp Pharmacol. 2009; (191):341-366). CNP is indicated for cardiac remodeling and the treatment of acute myocardial infarction, smooth muscle relaxation, and hypertension (Nakagawa and Saito, Biology 2022, 11, 1017). Perez-Ternero et al., PNAS 2022, vol 119 / 13 e2116470119, reported that C-type natriuretic peptide is a crucial regulator of metabolic homeostasis. CNP exerts its metabolic regulatory effects by inhibiting sympathetic neuronal thermogenesis programming via Gi-coupled natriuretic peptide receptor (NPR)-C and reducing the expression of peroxisome proliferator-activated receptor-γ coactivator-1α, while simultaneously driving adipogenesis via NPR-B / protein kinase-G. Perez-Ternero et al., Front. Mol. Neurosci. 15:991112. doi:10.3389 / fnmol.2022.991112, reported from CNP-deficient mice that CNP plays a role in regulating the blood-brain barrier and motor responsiveness to novel environments, and in particular, that CNP deficiency in gbCNP- / - mice results in weight loss but no change in muscle mass.

[0023] Another example of an FGFR3 inhibitor that acts on a downstream pathway of FGFR3 itself is meclizine, a molecule that attenuates the MAPK signaling pathway at the level of ERK phosphorylation (see, for example, Kitoh et al 2020. PLoS ONE 15(4):e0229639. https: / / doi.org / 10.1371 / journal.pone.0229639).

[0024] Mackler et al., 1973 (Arch. Biochem and Biophys 159, 885-888) reported that oxidative energy production is reduced in adult achondroplasia (ACH). Domondon et al., Am J Physiol Renal Physiol 2019 317:F1164-F1168 outlined the regulation of mitochondrial function by natriuretic peptides and emphasized the role of ANP and BNP / NPR-A activation in mitochondria. Miyashita et al., Diabetes 2009 58, 2880-2892 reported that the BNP / cGK cascade promotes muscle mitochondrial biosynthesis and fatty acid synthesis, and may prevent obese BNP-TG mice.

[0025] In contrast, Perez-Ternero et al., PNAS 2022 Vol. 119 No. 13 e2116470119 reported that CNP has a conservative function in regulating metabolic homeostasis, suppressing sympathetic thermogenesis programming via NPR-C while simultaneously driving adipogenesis via NPR-B / protein kinase-G, indicating that CNP has an effect opposite to that of NPR-A ANP / BNP activation. PGC-1 alpha is an important regulator of mitochondrial biosynthesis, and as reported in Domondon 2018, PGC-1 alpha is positively regulated via ANP and BNP. [Prior art documents] [Non-patent literature]

[0026] [Non-Patent Document 1] Takken et al., Journal of Pediatrics 2017, Vol 150, pp26-30 [Non-Patent Document 2] Patient Guide to Achondroplasia, John Hopkins Dept. Orthapaedic Surgery, 2003 [Non-licensed document 3] Sims et al., J Appl Physiol (1985) 2018 Mar 1;124(3):696-703

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Summary of the Invention

[0027] Description of the Invention Treatment for achondroplasia has focused on promoting cartilaginous bone growth, and therapeutic agents have been selected for their ability to improve the ring growth / height rate in children with achondroplasia. Surprisingly, the inventors of this invention have found that treating children with achondroplasia with the CNP formulation TransCon CNP (navepegritide) results in improved physical function, a reduction in adverse events associated with achondroplasia, and even correction of spinal malformations, such as kyphosis, particularly thoracolumbar kyphosis.

[0028] Based on the studies reported below, these improvements in physical function may be at least partially attributable to improved muscle function independently of bone growth, or the positive effects observed in, for example, spinal malformations may be attributable to improved bone growth, e.g., improved vertebral morphology, or a combination of effects on bone growth (e.g., improved vertebral morphology) and improved physical function. Children given placebo showed decreased physical performance and a significantly increased incidence of adverse events associated with achondroplasia. Furthermore, in a mouse model of achondroplasia, treatment with TransCon CNP was shown to increase the survival rate of pups within 15 days of birth. This finding correlated with a reduction in the incidence of maternal infanticide, a phenomenon associated with pup muscle weakness, and occurred in a timeframe not consistent with the effects on bone growth. These findings that CNP, an FGFR3 signaling inhibitor (as mentioned above, CNP inhibits FGFR3-mediated signaling), is effective in enhancing physical performance and muscle function, independently of enhanced chondrodic bone growth, indicate that CNP and other FGFR3 inhibitory strategies are suitable therapies for improving muscle function in both children and adults, for example, in the treatment of hypotonia and related disorders. Binding of CNP to the NPR-B receptor may contribute to its mechanism of action, and such NPR-B receptor agonists are also intended for this application. Binding of CNP to the NPR-C receptor may also contribute to its mechanism of action, and such NPR-C receptor agonists are also intended for this application.

[0029] The present invention provides a method for treating spinal malformations in a subject requiring treatment, the method comprising the steps of administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist and / or an NPR-C agonist to the subject, and treating the subject thereby. For further embodiments of the method for treating spinal malformations, see item list A.

[0030] The present invention provides FGFR3 signaling inhibitors, NPR-B agonists and / or NPR-C agonists for use in the treatment of spinal malformations, such as thoracolumbar malformations, in human subjects, such as human subjects with chondrodysplasia. For embodiments relating to the use of FGFR3 signaling inhibitors, NPR-B agonists and / or NPR-C agonists for use in the treatment of spinal malformations, please refer to item list B, and for therapeutic methods in which FGFR3 signaling inhibitors, NPR-B agonists and / or NPR-C agonists may be used, please refer to item list A.

[0031] The present invention provides FGFR3 signaling inhibitors, NPR-B agonists and / or NPR-C agonists for use in the treatment of thoracolumbar kyphosis in human subjects, for example, human subjects with chondrodysplasia.

[0032] The present invention provides an NPR-B agonist and / or NPR-C agonist for use in the treatment of spinal malformations, such as thoracolumbar malformations, in human subjects, such as human subjects with chondrodysplasia.

[0033] The present invention provides an NPR-B agonist and / or NPR-C agonist for use in the treatment of thoracolumbar kyphosis in human subjects, for example, human subjects with chondrodysplasia.

[0034] The present invention provides C-type natriuretic peptides (CNPs), such as nabepeglitide or bosolitide, for use in the treatment of spinal malformations, such as thoracolumbar malformations, in human subjects, such as human subjects with chondrodysplasia.

[0035] The present invention provides a type C natriuretic peptide (CNP), such as nabepeglitide or bosolitide, for use in the treatment of thoracolumbar kyphosis in human subjects, for example, human subjects with chondrodysplasia.

[0036] The present invention provides a type C natriuretic peptide (CNP), such as nabepeglitide or bosolitide, for use in the treatment of chondrodysplasia, wherein the use results in the treatment of thoracolumbar kyphosis in subjects having chondrodysplasia.

[0037] The present invention provides a method for treating spinal malformations in a subject requiring treatment, the method comprising the steps of administering a therapeutically effective amount of an NPR-B agonist and / or an NPR-C agonist to the subject, and treating the subject thereby.

[0038] The present invention provides a method for treating kyphosis, such as thoracic kyphosis or thoracolumbar kyphosis, in a subject requiring treatment, the method comprising the steps of administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist and / or an NPR-C agonist to the subject, and treating the subject thereby. [Means for solving the problem]

[0039] In some embodiments, the spinal malformation is unfixed thoracolumbar kyphosis.

[0040] A method for treating spinal malformations may optionally include a step of measuring or diagnosing the spinal malformation before, and optionally during and / or after, the treatment. The measurement and / or diagnosis may be performed during routine patient monitoring, and may be performed routinely at regular intervals over a treatment period of at least about six months or at least about one year, and may be performed during the treatment or treatment period, for example, every three months, or every six months, or every nine months, or every year. In some embodiments, the medical applications of the present invention are directed to patients who have undergone one or more measurement steps described herein.

[0041] In some embodiments, the spinal malformation is or includes a vertebral morphological malformation, such as a gibbs malformation, and the treatment results in an improvement in vertebral morphology, such as a reduction in apical wedge formation of vertebrae L1 and / or L2.

[0042] In some embodiments, the measurement of one or more spinal malformations is or includes vertebral morphometry of one or more vertebrae, e.g., thoracic and / or lumbar vertebrae, e.g., point morphometry.

[0043] In some embodiments, the measurement may include vertebral morphometry of vertebrae L1 and / or L2 using radiographs of vertebrae L1 and / or L2, and the treatment may result in a decrease in the PH / MW ratio of vertebrae L1 and / or L2.

[0044] In some embodiments, the measurement of spinal malformation(s) is or includes the measurement of the angle of curvature of the spine, for example, the Cobb angle, for example, the Cobb angle for scoliosis, the Cobb angle for kyphosis, the Cobb angle for thoracolumbar kyphosis, or the lumbar Cobb angle.

[0045] In some embodiments, the spinal malformation measurement(s) may include a measurement of thoracolumbar kyphosis (TLK), for example, the Cobb angle of thoracolumbar kyphosis measured between vertebrae T10-L2, T11-L2, or T12-L2.

[0046] In some embodiments, a Cobb angle of thoracolumbar kyphosis greater than approximately 20°, or greater than approximately 25°, or greater than approximately 30° indicates a patient requiring treatment for thoracolumbar kyphosis (TLK).

[0047] In some embodiments, the treatment results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, for example, by at least 3°, over a treatment period of at least about 6 months or at least about 12 months. In some embodiments, the treatment results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, for example, by at least 4°, over a treatment period of at least about 6 months or at least about 12 months. In some embodiments, the treatment results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, for example, by at least 5°, over a treatment period of at least about 6 months or at least about 12 months.

[0048] In some embodiments, the measurement(s) or monitoring is or includes a measurement of spinal malformations obtained from spinal radiographs, for example, from lateral radiographs taken from the subject.

[0049] In some embodiments, the measurement(s) or monitoring is or includes a spinal radiograph taken while the subject is standing, sitting, or supine, or obtained from an image or X-ray taken while the subject is standing, sitting, or supine.

[0050] In some embodiments, before and / or during the treatment period, the subjects are children (child subjects), e.g., children aged 0 to 18 years, e.g., children aged 0 to 14 years, e.g., children under 12 years, e.g., under 10 years, or under 8 years, or under 6 years, e.g., children under 5 years.

[0051] In some embodiments, the subject's epiphyses are open before and during treatment or the treatment period.

[0052] In some embodiments, the subject has a closed epiphysis before and / or during the treatment period.

[0053] In some embodiments, the subjects are at least 18 years old, for example, at least 25 years old, for example, at least 30 years old.

[0054] In some embodiments, the treatment method according to the present invention is performed or initiated in an infant or child aged 0 to 2 years, for example, 0 to 12 months, for example, 0 to 3 months or 0 to 6 months, who has been diagnosed with achondroplasia.

[0055] In some embodiments, the subject is diagnosed with achondroplasia. In some embodiments, the subject is diagnosed with a spinal malformation, e.g., thoracolumbar kyphosis and / or apical vertebral deviation or wedge formation (also referred herein as apical vertebral wedge formation) (see, for example, Margalitet et al., J Pediatr Orthop. 2018 Nov / Dec;38(10):491-497, incorporated herein by reference). In some embodiments, the subject is diagnosed with developmental delay, e.g., developmental motor delay. In some embodiments, developmental motor delay may be identified or diagnosed, for example, by the inability to sit or walk independently by 14 years or 30 months of age, respectively. In some embodiments, the subject has a cranial or cranial malformation, e.g., hydrocephalus, the presence of a ventriculoperitoneal shunt and foramen magnum decompression.

[0056] In some embodiments, the treatment is a preventative treatment. Preventative treatment may be used to prevent the development of spinal malformations.

[0057] In some embodiments, the treatment is corrective, for example, reducing the severity of a spinal malformation or preventing or reducing the progression of a spinal malformation.

[0058] In the treatment of achondroplasia, it is understood that initiating treatment during childhood or infancy may be preferable to provide more effective orthodontic or preventive / prophylactic treatment.

[0059] When spinal malformations become fixed, for example, when the epiphyses close, therapeutic effects can sometimes be obtained, for example, in adults, through improvements in muscle function and posture.

[0060] In some embodiments, the treatment method or use of the present invention further includes the use of a spinal support or spinal orthosis, such as a thoracolumbosacral orthosis (TLSO), before, during, or after the treatment / treatment period.

[0061] In some embodiments, the treatment method of the present invention further includes surgical correction or intervention of spinal malformations, such as thoracolumbar surgery or spinal fusion surgery, before, during, or after the treatment / treatment period.

[0062] In some embodiments, the medical applications of the present invention are directed towards patients receiving one or more of the above-described treatments (including, optionally, spinal support or surgical intervention).

[0063] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor to the subject.

[0064] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering a therapeutically effective amount of an NPR-B agonist to the subject.

[0065] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering a therapeutically effective amount of an NPR-C agonist to the subject.

[0066] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist to the subject.

[0067] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering a therapeutically effective amount of C-type natriuretic peptide (CNP) to the subject. In certain embodiments, the NPR-B agonist or CNP is bosolitide (SEQ ID NO: 30).

[0068] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, the method comprising the step of administering to the subject a therapeutically effective amount of C-type natriuretic peptide (CNP) (CNP is administered as a CNP conjugate and / or as a prodrug of CNP); or a pharmaceutically acceptable salt thereof.

[0069] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, the method comprising the step of administering to the subject a therapeutically effective amount of C-type natriuretic peptide (CNP) (CNP is administered as a CNP conjugate and / or as a prodrug of CNP); or a pharmaceutically acceptable salt thereof, the method comprising the step of administering to the subject a series of therapeutically effective amounts of CNP conjugate and / or a prodrug of CNP, wherein the sustained exposure of the patient to free CNP in the plasma between the series of administrations of therapeutically effective amounts of CNP conjugate and / or a prodrug of CNP is at least about 1 pmol / L. In certain embodiments, the series of administrations is administered, for example, once daily, once weekly, once every two weeks, or once monthly. In certain embodiments, the time interval between the series of administrations is at least about 24 hours, for example, at least about one week. In certain embodiments, the CNP conjugate or prodrug is a compound of formula (IIf'), a compound of formula (IIf), compound (1), or a pharmaceutically acceptable salt thereof.

[0070] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, the method comprising the step of administering to the subject a therapeutically effective amount of C-type natriuretic peptide (CNP) (CNP is administered as a CNP conjugate and / or as a prodrug of CNP); or a pharmaceutically acceptable salt thereof, wherein the CNP conjugate or prodrug of CNP is a compound of formula (IIf'), a compound of formula (IIf), compound (1), or a pharmaceutically acceptable salt thereof.

[0071] In certain embodiments, the subject is a human subject. In certain embodiments, the subject is a human subject under 18 years of age. In certain embodiments, the subject is a human subject at least 18 years of age. In certain embodiments, the subject has a closed epiphysis.

[0072] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering a therapeutically effective amount of C-type natriuretic peptide (CNP) to the subject, wherein the method comprises infusion of CNP into the subject, e.g., IV or SC infusion, wherein the infusion results in sustained exposure of the patient's plasma to CNP (free CNP) at a concentration of at least 1 pmol / L for a period of at least about 1 hour. In certain embodiments, sustained exposure of the patient's plasma to CNP (free CNP) for at least about 2 hours, e.g., at least about 4 hours, e.g., at least about 6 hours.

[0073] The present invention provides a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor to the subject, the FGFR3 signaling inhibitor (FGFR3 antagonist) being an FGFR3 tyrosine kinase inhibitor, for example, selected from the group consisting of infiglatinib, pemigatinib, futovatinib, erdafitinib, and TYRA-300.

[0074] The present invention provides a method (e.g., a therapeutic method) for improving muscle function in a subject.

[0075] The present invention provides a method (e.g., a therapeutic method) for improving skeletal muscle function in a subject.

[0076] The present invention provides a method (e.g., a treatment method) for improving muscle strength and / or muscle stamina (e.g., skeletal muscle strength and / or skeletal muscle stamina) in a subject.

[0077] The present invention provides a method (e.g., a treatment method) for improving myotonia (e.g., skeletal myotonia) in a subject.

[0078] In each case, the method includes administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-C agonist, or an effective amount of an NPR-B agonist to the subject. In a particular embodiment, the method includes administering an effective amount of an NPR-B / NPR-C agonist (e.g., CNP).

[0079] The subjects may have a disease or disorder that causes impairment of muscle function (e.g., muscle strength, stamina, and / or rigidity). The disease or disorder may cause impairment of skeletal muscle function.

[0080] Depending on the circumstances, FGFR3 signaling inhibitors, or NPR-B agonists, or NPR-C agonists, or CNP, such as CNP conjugates or prodrugs of CNP, or pharmaceutically acceptable salts thereof, may be used in combination with growth hormone, such as human growth hormone.

[0081] The present invention provides an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist for use in a method for improving muscle function in a subject, wherein the subject is optionally suffering from a disease or disorder that causes impaired muscle function.

[0082] The present invention provides an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist for use in a method for improving skeletal muscle function in a subject, wherein the subject is optionally suffering from a disease or disorder that causes impaired skeletal muscle function.

[0083] In certain embodiments, subjects have chondrodysplasia, for example, a disease selected from the group consisting of chondrodysplasia, hypochondroplasia, and lethal dysplasia of bone. Subjects are preferably human subjects. Subjects may be under 18 years of age or at least 18 years of age. Subjects may have closed epiphyses.

[0084] In certain embodiments, the FGFR3 signaling inhibitor is an FGFR3 antagonist or an NPR-B agonist.

[0085] In certain embodiments, an NPR-C agonist may be used in the method or use of the present invention.

[0086] FGFR3 antagonists may include fibroblast growth factor receptor (FGFR)3 tyrosine kinase inhibitors, anti-FGFR3 antibodies, anti-FGFR3 antisense oligonucleotides, or anti-FGFR3 siRNAs. Preferred NPR-B agonists are type C natriuretic peptides or their conjugates or prodrugs. Preferred NPR-C agonists are type C natriuretic peptides or their conjugates or prodrugs.

[0087] Examples of FGFR3 antagonists include fibroblast growth factor receptor (FGFR)3 tyrosine kinase inhibitors, such as infigratinib, pemigatinib, futovatinib, erdafitinib, or TYRA-300. Such FGFR3 antagonists are disclosed in WO2022147246A1, which is incorporated herein by reference in its entirety.

[0088] The present invention provides a method for improving muscle function (e.g., skeletal muscle function) in a subject suffering from a disease or condition that impairs muscle function (e.g., skeletal muscle function), wherein the method includes the step of administering a therapeutically effective amount of CNP.

[0089] The present invention relates to a method for improving muscle function (e.g., skeletal muscle function) in a subject suffering from a disease or condition that impairs muscle function (e.g., skeletal muscle function), the method comprising the step of administering a therapeutically effective amount of vosolitide.

[0090] In certain embodiments, CNP comprises or consists of SEQ ID NO: 24. In certain embodiments, CNP comprises or consists of peptides selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, and SEQ ID NO: 90. In some embodiments, CNP is a CNP conjugate or a pharmaceutically acceptable salt thereof comprising a CNP selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, and SEQ ID NO: 90.

[0091] Improvements in muscle function may include, for example, a) increased muscle (e.g., skeletal muscle) strength, b) increased muscle (e.g., skeletal muscle) tone, c) increased muscle (e.g., skeletal muscle) stamina, d) increased muscle (e.g., skeletal muscle) mass, e) decreased muscle (e.g., skeletal muscle) fatigue, f) increased cardiovascular endurance, g) improved cardiovascular health, h) decreased exercise intolerance, i) increased athletic performance, j) decreased exercise-induced fatigue, or k) increased muscle tone.

[0092] Administration of an effective dose of an FGFR3 signaling inhibitor, an effective dose of an NPR-B agonist, or an effective dose of an NPR-C agonist can result in an increase in muscle mass (e.g., skeletal muscle) and / or skeletal muscle / fat ratio in the subject.

[0093] Administration of an effective dose of an FGFR3 signaling inhibitor, an effective dose of an NPR-B agonist, or an effective dose of an NPR-C agonist may result in the treatment or prevention of musculoskeletal pain, improvement of posture or reduction of abnormal spinal curvature, improvement of kyphosis, e.g., thoracolumbar kyphosis (TLK), lordosis, e.g., lumbar lordosis, spinal stenosis, or scoliosis, improvement of sleep apnea syndrome, obstructive sleep apnea syndrome, otitis media, or reduction of obesity. These improvements may result from improved muscle function (e.g., skeletal muscle function). Therefore, the treatment, prevention, or improvement of any of the conditions mentioned above is preferably due to improved muscle function (e.g., skeletal muscle function).

[0094] In certain embodiments, CNP is administered as a prodrug. In certain embodiments, the CNP prodrug provides sustained exposure to the active CNP peptide after administration to the subject.

[0095] The prodrug may, in some cases, be a compound of formula (IIf') or formula (IIf), or compound (1), or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments where the subjects are adult humans (i.e., at least 18 years of age), the subjects may have been treated with an FGFR3 signaling inhibitor, or an NPR-B agonist (e.g., CNP), or an NPR-C agonist prior to age 18. Therefore, the present invention provides a therapeutic treatment that is initiated before age 18 and continued beyond age 18.

[0097] Administration of FGFR3 signaling inhibitors, NPR-B agonists, or NPR-C agonists is appropriate. a) Increase in skeletal muscle strength, b) Increased skeletal muscle tone, c) Increase in skeletal muscle stamina, d) Increase in skeletal muscle mass, e) Reduction of skeletal muscle fatigue, f) Increase in cardiovascular endurance, g) Increased cardiovascular health, h) Reduced exercise intolerance, i) Increase in athletic ability, j) Reduction of exercise-induced fatigue, and k) hypotonia It can result in improvement of one or more muscle functions selected from the group consisting of the following:

[0098] Thus, the present method can be described as an alternative method for increasing skeletal muscle strength in a subject (in which case the subject is suffering from a disease or condition that impairs muscle, e.g., skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0099] The method may also be described as a method for increasing skeletal muscle tone in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0100] The method may also be described as a method for increasing skeletal muscle stamina in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0101] The method may also be described as a method for increasing skeletal muscle mass in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0102] The method may also be described as a method for reducing skeletal muscle fatigue in a subject (where the subject is suffering from a disease or condition that impairs muscle function, e.g., skeletal muscle function), and the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0103] The method may also be described as a method for increasing cardiovascular endurance in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0104] The method may also be described as a method for increasing cardiovascular health in a subject (where the subject is suffering from a disease or condition that impairs muscle function, e.g., skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0105] The method may also be described as a method for reducing exercise intolerance in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0106] The method may also be described as a method for increasing exercise capacity in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0107] The method may also be described as a method for reducing exercise-induced fatigue in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0108] The method may also be described as a method for reducing hypotonia in a subject (where the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0109] Administration of an FGFR3 signaling inhibitor, or an effective dose of an NPR-B agonist, or an NPR-C agonist may result in an increase in the skeletal muscle / fat ratio in a subject, and the method may be framed as an alternative method for increasing the skeletal muscle / fat ratio in a subject (where the subject may be suffering from a disease or condition that impairs muscle, e.g., skeletal muscle function), wherein the method comprises the step of administering an effective dose of an FGFR3 signaling inhibitor, or an effective dose of an NPR-B agonist, or an effective dose of an NPR-C agonist to the subject.

[0110] Administration of an FGFR3 signaling inhibitor, or an effective dose of an NPR-B agonist, or an NPR-C agonist may cause hypotonia in a subject. Therefore, the present method may be framed as a method for reducing hypotonia in a subject (where the subject may be suffering from a disease or condition that impairs muscle function, e.g., skeletal muscle function), the method comprising the step of administering an effective dose of an FGFR3 signaling inhibitor, or an effective dose of an NPR-B agonist, or an effective dose of an NPR-C agonist to the subject. Accordingly, the present method may be described as a method for treating hypotonia in a subject.

[0111] Administration of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an NPR-C agonist may cause a reduction in musculoskeletal pain in a subject. Therefore, the present method may be framed as a method for treating, preventing, or reducing musculoskeletal pain in a subject (where the subject is suffering from a disease or condition that impairs muscle function, e.g., skeletal muscle function), wherein the method comprises the step of administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to the subject.

[0112] The method also results in improved posture and correction of abnormal spinal curvature, and therefore the method may be framed as a method for improving posture or treating abnormal spinal curvature in a subject (where the subject may be suffering from a disease or condition that impairs muscle function, e.g., skeletal muscle function), wherein the method comprises the step of administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to the subject. The method can result in improved kyphosis, e.g., thoracolumbar kyphosis (TLK), lordosis, e.g., lumbar lordosis, or scoliosis, and therefore the method may be defined as a method for treating one or more of these conditions in a subject (where the subject may be suffering from a disease or condition that impairs muscle function, e.g., skeletal muscle function), wherein the method comprises the step of administering an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to the subject.

[0113] This method may result in improvement of sleep apnea, snoring, obstructive sleep apnea, and otitis media, and such method can be defined as a method for treating one or more of these conditions in a subject (where the subject may have a disease or condition that impairs muscle function, e.g., skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist. A reduction in the incidence, prevalence, and / or severity of sleep apnea, snoring, obstructive sleep apnea, and otitis media may occur.

[0114] The present method may result in a reduction of obesity, and such a method can be defined as a method for reducing obesity in a subject (in which case the subject is suffering from a disease or condition that impairs muscle function, such as skeletal muscle function), wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0115] The present invention provides a method for treating kyphosis in a patient requiring treatment for kyphosis, the method comprising the step of administering an effective amount of CNP, CNP conjugate, or a pharmaceutically acceptable salt or unit dosage form thereof to the patient, thereby treating the kyphosis. Kyphosis is a condition in which the upper part of the spine curves outward abnormally, causing the upper back to become rounded, and is sometimes called "hunchback." It may occur alone or in conjunction with scoliosis. In some embodiments, the kyphosis is postural kyphosis. In some embodiments, the kyphosis is thoracic kyphosis or thoracolumbar kyphosis.

[0116] The present invention provides a method for treating thoracolumbar kyphosis in a subject requiring treatment, the method comprising the step of administering an effective amount of an NPR-B agonist, CNP, CNP conjugate, or a pharmaceutically acceptable salt or unit dosage form thereof to the subject, thereby treating the thoracolumbar kyphosis.

[0117] The present invention provides a method for treating thoracolumbar kyphosis in a subject requiring treatment, the method comprising administering an effective amount of an NPR-B agonist, CNP, CNP conjugate, or a pharmaceutically acceptable salt or unit dosage form thereof to the subject, thereby treating the thoracolumbar kyphosis, the subject being under 18 years of age, for example under 14 years, for example under 12 years, for example under 10 years, for example under 8 years, for example up to 6 years, or up to 5 years. In some embodiments, the present invention provides the method wherein the subject is at least 5 years of age.

[0118] In certain embodiments, the patient is diagnosed with a bone dysplasia or bone disorder, selected from the group consisting of chondrodysplasia, hypochondrodysplasia, short stature, Noonan syndrome, and SHOX deficiency.

[0119] The present invention also provides a method for treating foramen stenosis in a patient requiring treatment for foramen stenosis, the method comprising the step of administering an effective amount of CNP, CNP conjugate, or a pharmaceutically acceptable salt or unit dosage form thereof to the patient, thereby treating the foramen stenosis. In some embodiments, the patient has chondrodysplasia.

[0120] The present invention also provides a method for treating otitis media or an ear infection in a patient, or a method for reducing the incidence of ear infections in a patient requiring such treatment, wherein the method comprises the step of administering to the patient a therapeutically effective amount of CNP, CNP conjugate, or a pharmaceutically acceptable salt or unit dosage form thereof, thereby treating otitis media or an ear infection or reducing the incidence of ear infections. In some embodiments, the patient has chondrodysplasia.

[0121] The present invention also provides a method for treating sleep apnea syndrome in a patient requiring treatment for sleep apnea syndrome, the method comprising the step of administering to the patient a therapeutically effective amount of CNP, CNP conjugate, or a pharmaceutically acceptable salt or unit dosage form thereof. For example, the treatment can reduce the incidence of sleep apnea or reduce the severity of sleep apnea. In some embodiments, the patient has chondrodysplasia.

[0122] The present invention also provides a method for reducing the frequency of adverse events associated with achondroplasia in a patient diagnosed with achondroplasia, the method comprising the step of administering a therapeutically effective amount of CNP, CNP conjugate, or a pharmaceutically acceptable salt or unit dosage form thereof, wherein the patient may be a pediatric patient and / or a patient with open epiphysis.

[0123] The present invention provides a method for improving or enhancing the emotional well-being of a subject, the method comprising the step of administering an effective amount of an NPR-B agonist to the subject, and optionally including the step of monitoring the subject's emotional stability, for example, before, during, and / or after the treatment period, using, for example, the ACEM emotional well-being index.

[0124] The present invention provides a method for improving or enhancing the daily living functions of a subject, the method comprising the step of administering an effective amount of an NPR-B agonist to the subject, and optionally including the step of monitoring the subject's daily living functions, for example, before, during, and / or after the treatment period, using, for example, the ACEM daily living function index.

[0125] In any of the above methods, the subjects may have chondrodysplastic disorders, such as those selected from the group consisting of chondrodysplasia, hypochondrodysplasia, and lethal dysplasia of bone.

[0126] In the above method, the subjects may have chondrodysplasia. In some embodiments, the subjects do not have chondrodysplasia.

[0127] In all of the above methods, subjects may have chondrodysplasia, and subjects must be at least 18 years old or have closed epiphyses.

[0128] To the extent that methods are referenced herein, the present invention also provides an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist for use in such methods, and the use of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist in the manufacture of a pharmaceutical for use in such methods.

[0129] In certain embodiments, CNP is in the form of a unit dosage form comprising a CNP conjugate or a pharmaceutically acceptable salt thereof.

[0130] In certain embodiments, the unit dosage form of CNP comprises a therapeutically effective amount of CNP conjugate or a pharmaceutically acceptable salt thereof, in which the CNP portion is reversibly conjugated to the polymer portion. [Brief explanation of the drawing]

[0131] [Figure 1] This figure shows the survival rate (survival rate observation) of Fgfr3Y367C / + offspring during the study period (16 days), comparing groups treated with compound (1) at 5.6 mg / kg / day (solid line), compound (1) at 1.2 mg / kg every 3 days (dashed line), or vehicle alone (dotted line). [Figure 2] This figure shows the changes in pedicle width (calibrated) after 52 weeks of treatment (cohorts 3 and 4) compared to placebo, as detailed in Example 14. This data shows a trend of increased pedicle width with treatment compared to placebo (PLA). [Figure 3]This figure shows the change in mean hand length after 52 weeks in the treatment (Cohorts 3 and 4) compared to placebo (PLA), as detailed in Example 15. The results clearly show a dose-dependent increase in hand length with treatment. [Figure 4] This figure shows the measurement of thoracolumbar kyphosis based on lateral radiographs obtained from subjects at baseline and 52 weeks after treatment with placebo (PLA) or compound (1) (100 μg) at 100 μg / kg in the Phase II study reported in Example 4 (above). Panels A to C show box plots for the median ± 5 to 95th percentile. Panel A shows a statistically significant decrease in the degree of thoracolumbar kyphosis 52 weeks after treatment with compound 1, and further shows a corresponding statistically significant decrease in the achondroplasia (ACH)-related Z score (Panel B) and a statistically significant decrease in the healthy control Z score (Panel C). Panel D shows how the degree of change in both lumbar lordosis and thoracic kyphosis (TLK) was measured from lateral radiographs. [Figure 5] This is a schematic diagram of 10 points measured by 10-point morphological measurements in a cross-section of a vertebral bone (L1, X-ray). PH = posterior height, MH = middle height (MH is measured at 50% of the lower width), AH = anterior height, MW = middle width. LW = lower width. In cases of cuneate vertebral malformations (typically L1 or L2) commonly seen in chondrodysplasia, a decrease in the PH / MW ratio indicates normalization of vertebral morphology (e.g., a decrease in apical cuneiform formation). [Figure 6] This figure shows the reduction in spinal malformations in subjects of Cohort 4 at baseline (6A, subjects aged 5.3 years) and after 52 weeks of treatment with compound (1) at 100 μg / kg / week (6B, subjects aged 6.3 years). [Figure 7] Figures 6A and 6B show close-ups of lateral radiographs of the subjects, illustrating the normalization of the L1 vertebra after 52 weeks of treatment, corresponding to a reduction in thoracolumbar kyphosis (TLK). Figure 7A was obtained from a baseline radiograph, and Figure 7B was obtained from a radiograph after 52 weeks of treatment. [Modes for carrying out the invention]

[0132] definition In this specification, the term “about” used in combination with a number is used to indicate a range of plus / minus 10% or less of the number, in a particular embodiment, 8% or less of the number, in a particular embodiment, 5% or less of the number, and in a particular embodiment, 2% or less of the number. For example, the phrase “about 200” is used to mean a range of 200+ / -10%, i.e., 180 to 220; in a particular embodiment, a range of 200+ / -8%, i.e., 184 to 216; in a particular embodiment, a range of 200+ / -5%, i.e., 190 to 210; and in a particular embodiment, a range of 200+ / -2%, i.e., 196 to 204. A percentage indicated as “about 20%” does not mean “20%+ / -10%,” i.e., a range of 10 to 30%, but it is understood that “about 20%” means a range of 18 to 22%, i.e., plus / minus 10% of the number 20.

[0133] As used herein, the term “antimicrobial agent” refers to chemical substances such as chemicals that kill or inhibit the growth of microorganisms such as bacteria, fungi, yeasts, protozoa, and molds, and / or destroy viruses.

[0134] As used herein, the terms “buffer” or “buffering agent” refer to compounds that maintain pH within a desired range. Physiologically tolerable buffers include, for example, sodium phosphate, succinates, histidine, bicarbonates, citrates, acetates, sulfates, nitrates, chlorides, and pyruvates. Antacids such as Mg(OH)2 or ZnCO3 may also be used.

[0135] As used herein, the term “CNP” refers, in certain embodiments, to all CNP polypeptides derived from mammalian species, e.g., human and mammalian species, particularly human and mouse species, as well as their variants, analogs, orthologues, homologs, and derivatives, and their fragments, which are characterized by regulating the growth, proliferation, and differentiation of chondrocytes of the chondrocyte growth plate. Human prepro-CNP, containing 126 amino acids, is further cleaved to obtain CNP-53 and CNP-22. The term “CNP” also includes all CNP variants, analogs, orthologues, homologs, derivatives, and their fragments. CNP variants, analogs, orthologues, homologs, derivatives, and their fragments disclosed in WO 2009 / 067639 A2 and WO 2010 / 135541 A2 are incorporated herein by reference. CNP peptides and pharmaceutical compositions containing CNP peptides are disclosed in WO2009 / 067639, WO2010 / 135541, WO2017 / 020034, WO2017 / 100400, WO2021055497, WO2021 / 030411, WO2023 / 283657, and WO2022 / 115563, all of which are incorporated herein by reference. Exemplary CNP peptides are provided herein and include bosolitide. Regardless of the length of the CNP moiety, the sequence of the ring portion of wild-type CNP is FGLKLDRIGSMSGLG (SEQ ID NO: 96).

[0136] The term "C" as used herein 1-4 The term "alkyl," alone or in combination, refers to a linear or branched alkyl group having 1 to 4 carbon atoms. When present at the end of a molecule, it refers to a linear or branched C group. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Two parts of the molecule are C 1-4 When bonded by alkyl, such C 1-4 Examples of alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, and -C(CH3)2-. 1-4Each hydrogen of the alkyl carbon may optionally be substituted by the substituents defined above. Optionally, C 1-4 one or more of the following defined moieties may be inserted into the alkyl.

[0137] As used herein, the term "C 1-6 alkyl" alone or in combination means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms. When present at the end of a molecule, examples of straight and branched chain C 1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl. When two moieties of a molecule are joined by a C 1-6 alkyl group, examples of such C 1-6 alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)- and -C(CH3)2-. Each hydrogen atom of C 1-6 carbon may optionally be substituted by the substituents defined above. Optionally, C 1-6 one or more of the following defined moieties may be inserted into the alkyl. [[ID=二十]]

[0138] [[ID=二十一]] [[ID=二十二]] Thus, "C 1-10 alkyl", "C 1-20 alkyl" or "C 1-50 alkyl" each means an alkyl chain having from 1 to 10, 1 to 20, or 1 to 50 carbon atoms, where each hydrogen atom of C 1-10 C 1-20 or C 1-50 carbon may optionally be substituted by the substituents defined above. Optionally, one or more of the following defined moieties may be inserted into C 1-10 C 1-20 alkyl or C 1-50 alkyl.

[0139] The term "C" as used herein 2-6 The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon portion, either alone or in combination, having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. When present at the ends of a molecule, examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3, and -CH=CH-CH=CH2. Two parts of the molecule are C 2-6 When bonded with an alkenyl group, such C 2-6 An example of an alkenil is -CH=CH-. 2-6 Each hydrogen atom of the alkenyl moiety may optionally be substituted by a substituent as defined above. Optionally, C 2-6 An alkenil may have one or more parts, as defined below, inserted into it.

[0140] Therefore, "C 2-10 Alkenil, "C 2-20 "Alkenil" or "C 2-50 The term "alkenyl" refers to a linear or branched hydrocarbon portion, either alone or in combination, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms and containing at least one carbon-carbon double bond. 2-10 Alkenil, C 2-20 Alkenyl or C 2-50 Each hydrogen atom of the alkenyl group may be optionally substituted by a substituent as defined above. Optionally, C 2-10 Alkenil, C 2-20 Alkenyl or C 2-50 An alkenil may have one or more parts, as defined below, inserted into it.

[0141] The term "C" as used herein 2-6The term "alkynyl" refers, alone or in combination, to a linear or branched hydrocarbon moiety containing at least one carbon-carbon triple bond, having 2 to 6 carbon atoms. When present at the end of a molecule, examples include -C≡CH, -CH2-C≡CH, CH2-CH2-C≡CH, and CH2-C≡C-CH3. When two parts of a molecule are linked by an alkynyl group, an example is -C≡C-. 2-6 Each hydrogen atom of the alkynyl group may optionally be substituted by substituents as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-6 Alkinyl may have one or more parts, as defined below, inserted into it.

[0142] Therefore, as used herein, "C 2-10 Alkinyl, C 2-20 "Alkinyl" and "C 2-50 The term "alkynyl" refers to a linear or branched hydrocarbon moiety, either alone or in combination, having 2 to 10, 2 to 20, or 2 to 50 carbon atoms and containing at least one carbon-carbon triple bond. 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 Each hydrogen atom of the alkynyl group may optionally be substituted by substituents as defined above. Optionally, one or more double bonds may be present. Optionally, C 2-10 Alkinyl, C 2-20 Alkinyl or C 2-50 Alkinyl may have one or more parts, as defined below, inserted into it.

[0143] As stated above, C 1-4 Alkyl, C 1-6 Alkyl, C 1-10 Alkyl, C 1-20 Alkyl, C 1-50 Alkyl, C 2-6 Alkenil, C 2-10 Alkenil, C 2-20 Alkenil, C 2-50 Alkenil, C 2-6Alkinyl, C 2-10 Alkinyl, C 2-20 Alkenyl or C 2-50 The alkynyl may have one or more parts interspersed within it, and in a particular embodiment, the one or more parts are [ka] (In the formula, The dashed line indicates binding to the aforementioned portion or the remainder of the reagent. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.) It is selected from the group consisting of the following.

[0144] The term "C" as used herein 3-10 The term "cycloalkyl" means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. 3-10 Each hydrogen atom of the cycloalkyl carbon may be substituted with a substituent as defined above. 3-10 "Cycloalkyl" also includes cross-linked birings such as norbornane or norbornene.

[0145] As used herein, the terms “8-30 membered carbopolycyclil” or “8-30 membered carbopolycycle” mean a cyclic portion of two or more rings having 8 to 30 ring atoms, where two adjacent rings share at least one ring atom, and which may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic rings). In certain embodiments, an 8-30 membered carbopolycyclil means a cyclic portion of 2, 3, 4, or 5 rings, and in certain embodiments, a cyclic portion of 2, 3, or 4 rings.

[0146] As used herein, the terms “3- to 10-membered heterocyclyl” or “3- to 10-membered heterocycle” mean a ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, which may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic rings), in which at least one ring atom and up to four ring atoms are substituted by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and which are bonded to the remainder of the molecule via carbon or nitrogen atoms. Examples of heterocycles with 3 to 10 members include, but are not limited to, aziridine, oxirane, thiirane, azirine, oxilen, thiirane, azetidine, oxetane, thietan, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazole, tetrahydrofuran, Examples include tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidin, isothiazolidine, thiadiazolidin, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidin, diazepane, azepine, and homopiperazine. Each hydrogen atom of a 3-10 membered heterocyclyl or 3-10 membered heterocyclic group may be substituted with a substituent as defined below.

[0147] As used herein, the terms “8-11 membered heterobicyryl” or “8-11 membered heterobicyclic” mean a heterocyclic part having 8-11 ring atoms, wherein at least one ring atom is shared by both rings and may contain up to a maximum number of double bonds (fully saturated, partially saturated, or unsaturated aromatic or non-aromatic rings), wherein at least one and up to six ring atoms are substituted by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the rings are bonded to the remainder of the molecule via carbon or nitrogen atoms. Examples of 8- to 11-membered heterobicyclic rings include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzimidazole, benzimidazolin, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine, and pteridine. The term 8- to 11-membered heterobicyclic ring also includes bicyclic spiro structures such as 1,4-dioxa-8-azaspiro[4.5]decane, or bridging heterocyclic rings such as 8-aza-bicyclo[3.2.1]octane. Each hydrogen atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicyclic carbon may be substituted by substituents as defined below.

[0148] Similarly, the terms “8-30 membered heteropolycyclil” or “8-30 membered heteropolycycle” mean a heterocyclic part of three or more rings, in particular embodiments three, four or five rings having 8 to 30 ring atoms, wherein two adjacent rings share at least one ring atom and may contain up to a maximum number of double bonds (fully saturated, partially saturated or unsaturated aromatic or non-aromatic rings), where at least one ring atom, up to a maximum of ten ring atoms, is substituted by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen, and nitrogen (including =N(O)-), and the rings are bonded to the remainder of the molecule via carbon or nitrogen atoms.

[0149] The following structure: [ka] Regarding the part, "Pair R x / R y Together with the atoms to which they are bonded, C 3-10 The phrase "forms a cycloalkyl or a 3-10 member heterocycline" is R x and R y However, the structure is as follows: [ka] (In the formula, R is C 3-10 (It is a cycloalkyl or a 3-10 membered heterocycline.) It is understood that this means forming something.

[0150] The following structure: [ka] Regarding the part, "Pair R x / R y The phrase "they, together with the atoms to which they are bonded, form ring A" is R x and R y However, the structure is as follows: [ka] It is also understood to mean forming something.

[0151] As used herein, the term “CNP polypeptide variant” refers to a polypeptide derived from the same species but distinct from the reference CNP polypeptide. Generally, the differences are limited, so the amino acid sequences of the reference and the variant are closely similar as a whole and identical in many regions. In certain embodiments, the CNP polypeptide variant is at least 70%, 80%, 90%, or 95% identical to the reference CNP polypeptide. A polypeptide having an amino acid sequence that is, for example, at least 95% “identical” to the query amino acid sequence is intended to be identical to the query sequence, except that the amino acid sequence of the target polypeptide may contain no more than 5 amino acid changes per 100 amino acids of the query amino acid sequence. These changes in the reference sequence may occur individually scattered between residues in the reference sequence, or scattered between one or more adjacent groups in the reference sequence, at the amino-terminus (N-terminus) or carboxy-terminus (C-terminus) of the reference amino acid sequence, or anywhere between these terminal positions. The query sequence may be the entire amino acid sequence of the reference sequence, or any fragment as specified herein. Such CNP polypeptide variants may be isoforms encoded by native variants, such as native allele variants encoded by one of several alternative forms of CNP occupying a given locus of a chromosome or organism, or native splice variants derived from a single primary transcript. Alternatively, CNP polypeptide variants may be variants not known to occur naturally but that can be produced by mutagenesis techniques known in the art. It is known in the art that one or more amino acids can be deleted from the N-terminus or C-terminus of a bioactive peptide or protein with little loss of biological function. Such N-terminal and / or C-terminal deletions are also included in the term CNP polypeptide variant.

[0152] As used herein, the terms “dose” or “unit dose” refer to a predetermined amount of a drug, such as CNP, administered at one time to produce a certain biological response in a patient. The dose of a drug is determined by its inherent potency, in which case the amount is a therapeutic dose or therapeutic unit dose.

[0153] As used herein, the term “dosage form” refers to a physical shape containing an active pharmaceutical ingredient in combination with selected additional ingredients or excipients, intended to be delivered to a site of action in the body via various routes of drug administration. The term also refers to a physical shape that provides a precise mixture of the active pharmaceutical ingredient and excipients to aid in administration and delivery to the site of action, achieve rapid onset of action, and improve bioavailability. As used herein, the term “unit dosage form” refers to a dosage form configured for a single dose to a patient. For example, a unit dosage form may be a single vial or container containing a certain amount of drug suitable for a single dose.

[0154] As used herein, the term “administration regimen” refers to a combination of dose and frequency of drug administration. An administration regimen may also include the route of administration (e.g., subcutaneously) and / or duration of administration (e.g., until the patient reaches 18 years of age or epiphyseal closure). Administration of an administration regimen can maintain steady-state serum concentrations of CNP such that peaks, troughs, and area under the curve over specified intervals maintain a specified range of variation and / or the peak-to-trough ratio does not exceed a specified threshold.

[0155] As used herein, the term “drug” refers to a substance used in the treatment, cure, prevention or diagnosis of a disease, or otherwise used to enhance physical or mental well-being. When a drug, such as CNP, is conjugated into another part, the portion of the resulting product derived from the drug is referred to as the “drug moiety.”

[0156] As used herein, the term “excipient” refers to a compound administered together with a drug or drug conjugate, such as a buffer, isotonic modifier, preservative, stabilizer, adsorption inhibitor, antioxidant, or other adjuvant. However, in some examples, a single excipient may have a dual or triple function. The term “excipient” may also refer to a diluent, adjuvant, or vehicle with which the drug or drug conjugate is administered. Such pharmaceutical excipients may be sterile solutions, such as water, and oils, such as oils of petroleum, animal, plant, or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, and sesame oil. When the pharmaceutical formulation is administered orally, water is a preferred excipient. When the pharmaceutical formulation is administered intravenously or subcutaneously, physiological saline and glucose aqueous solutions are preferred excipients. In certain embodiments, physiological saline, glucose aqueous solutions, and glycerol solutions are used as liquid excipients for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monosetearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol. The pharmaceutical formulation may also contain small amounts of humectants or emulsifiers, pH buffers such as acetates, succinates, Tris (tris(hydroxymethyl)aminomethane), carbonates, phosphates, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), surfactants such as Tween®, poloxamer, poloxamine, CHAPS, Igepal®, or amino acids such as glycine, lysine, or histidine. These pharmaceutical formulations can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, and sustained-release formulations. Pharmaceutical formulations can also be formulated as suppositories using conventional binders and excipients, such as triglycerides.Oral formulations may contain standard excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Such formulations contain a therapeutically effective amount of the drug or drug portion, along with a suitable amount of excipients to provide a form for appropriate administration to the patient. The formulations should be adapted to the mode of administration.

[0157] As used herein, the terms “formulation” or “pharmaceutical formulation” refer to a formulation comprising one or more CNP conjugates and one or more excipients, and any product resulting directly or indirectly from any combination, complexation or aggregation of any two or more components of a composition, or from the dissociation of one or more of the above components, or from one or more of other types of reactions or interactions of the above components. Accordingly, the pharmaceutical formulations of the present invention encompass any formulation or composition made by mixing one or more CNP conjugates with pharmaceutically acceptable excipients, such as buffers and fillers.

[0158] As used herein, the term “free form” of a drug refers to the unmodified, pharmacologically fully active form of the drug after it has been released, for example, from a CNP conjugate or a pharmaceutically acceptable salt thereof.

[0159] As used herein, the term “functional group” means a group of atoms that can react with other groups of atoms. Examples of functional groups include, but are not limited to, carboxylic acids (-(C=O)OH), primary or secondary amines (-NH2, -NH-), maleimides, thiols (-SH), sulfonic acids (-(O=S=O)OH), carbonates, carbamates (-O(C=O)N<), hydroxyls (-OH), aldehydes (-(C=O)H), ketones (-(C=O)-), hydrazines (>NN<), isocyanates, isothiocyanates, phosphoric acids (-O(P=O)OHOH), phosphonic acids (-O(P=O)OHH), haloacetyls, alkyl halides, acryloyls, aryl fluorides, hydroxylamines, disulfides, sulfonamides, sulfuric acids, vinyl sulfones, vinyl ketones, diazoalkanes, oxiranes, and aziricin.

[0160] As used herein, the term "halogen" means fluoro, chloro, bromo, or iodine. The halogen is generally preferred to be fluoro or chloro.

[0161] As used herein, the term “interrupted” means that a portion is inserted between two carbon atoms, or, if the insertion is at one end of the portion, between a carbon or heteroatom and a hydrogen atom, or in certain embodiments, between a carbon atom and a hydrogen atom.

[0162] As used herein, the term "isotonicity agent" refers to a compound that minimizes pain, irritation, and tissue trauma that may result from cellular damage caused by osmotic pressure differences between an injected solution and plasma.

[0163] As used herein, the term “part” means a portion of a molecule that lacks one or more atoms compared to the corresponding reagent. For example, when a reagent of the formula “HXH” reacts with another reagent and becomes part of the reaction product, the corresponding part of the reaction product has the structure “HX-” or “-X-”, where each “-” indicates a bond to another part. Thus, the drug part, for example, the CNP part, is released from the conjugate as a drug, for example, CNP.

[0164] Where an arrangement or chemical structure of atomic groups bonded to two parts or intercepted to one part is provided, it is understood that, unless otherwise explicitly stated, such arrangement or chemical structure may bond to the two parts in any orientation. For example, part "-C(O)N(R 1 )-" is "-C(O)N(R 1 )-" or "-N(R 1 It can be joined to two parts as )C(O)- or inserted into one part. Similarly, part: [ka] teeth, [ka] as, or [ka] It can be joined into two parts, or it can be inserted into one part.

[0165] If the CNP moiety contains one or more acidic or basic groups, the unit dosage form also includes the corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular the pharmaceutically usable salts thereof. Therefore, CNP moieties containing one or more acidic groups may exist and can be used, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More detailed examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, triethanolamine, etc.) or amino acids, as well as other salts or amines known to those skilled in the art. CNP moieties containing one or more basic groups, i.e., protonable groups, may exist and can be used in the form of addition salts with inorganic or organic acids thereof. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. Further methods for converting basic groups to cations are known to those skilled in the art, such as alkylation of amine groups that yield suitable counterions for positively charged ammonium groups and their salts. When the CNP portion contains both acidic and basic groups, the pharmaceutical formulations according to the present invention also include intramolecular salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting these conjugates with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The unit dosage forms according to the present invention also include all salts of CNP conjugates, which, although not directly suitable for use in pharmaceuticals due to their low physiological compatibility, can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0166] As used herein, the term “patient” refers to a subject suitable for treatment or prevention according to the present invention, in particular a human subject.

[0167] As used herein, the term “pharmaceutically acceptable” means a substance that does not cause harm when administered to a patient and is preferably approved by a regulatory authority, e.g., the EMA (Europe) and / or the FDA (United States) and / or any other national regulatory authority for use in animals, and preferably for use in humans.

[0168] As used herein, the term “physiological conditions” refers to an aqueous buffer at pH 7.4 and 37°C.

[0169] As used herein, the term "polypeptide" refers to a chain of two to fifty amino acid monomers linked by peptide (amide) bonds. For CNP drugs and CNP moieties only, sequences with more than 50 amino acids are also referred to as "polypeptides" for simplicity.

[0170] As used herein, the term “preservative” refers to a chemical substance that has antimicrobial properties and prevents chemical degradation.

[0171] As used herein, the term "protein" preferably refers to a chain of more than 50 amino acid monomer moieties linked by peptide bonds, where 12,000 or fewer amino acid monomers, for example, 10,000 or fewer amino acid monomer moieties, 8,000 or fewer amino acid monomer moieties, 5,000 or fewer amino acid monomer moieties, or 2,000 or fewer amino acid monomer moieties are linked by peptide bonds.

[0172] As used herein, the term “polymer” means a molecule comprising repeating structural units, i.e., monomers, linked by chemical bonds in a linear, cyclic, branched, crosslinked, or dendrimer-like manner, or a combination thereof, which may be of synthetic origin, biological origin, or a combination of both. It is understood that the polymer may also include one or more other chemical groups and / or parts, such as one or more functional groups. In certain embodiments, a soluble polymer has a molecular weight of at least 0.5 kDa, e.g., at least 1 kDa, at least 2 kDa, at least 3 kDa, or at least 5 kDa. If the polymer is soluble, in certain embodiments it may have a molecular weight of up to 1000 kDa, e.g., up to 750 kDa, e.g., up to 500 kDa, e.g., up to 300 kDa, e.g., up to 200 kDa, e.g., up to 100 kDa.

[0173] Proteins or polypeptides are also understood to be polymers in which amino acids are repeating structural units, even though the side chains of each amino acid may differ.

[0174] As used herein, the terms “polymer” or “polymer part” mean a reagent or part comprising one or more polymers or polymer parts. A polymer reagent or part may also include one or more other parts, which in a particular embodiment are selected from the group consisting of: - C 1-50 Alkyl, C 2-50 Alkenil, C 2-50 Alkinyl, C 3-10 Cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, phenyl, naphthyl, indenyl, indanyl and tetralinyl; and - Groups including the following: [ka] (In the formula, The dashed line indicates binding to the above portion or the remaining reagent. -R and -R a (These are independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl, and hexyl.) A join selected from the options.

[0175] Those skilled in the art will understand that not all polymerization products obtained from a polymerization reaction have the same molecular weight, but rather exhibit a molecular weight distribution. Consequently, as used herein, molecular weight ranges, molecular weights, ranges of monomer numbers in a polymer, and monomer numbers in a polymer refer to the number-average molecular weight and monomer number average, i.e., the arithmetic mean of the molecular weight of the polymer or polymer moiety and the arithmetic mean of the monomer numbers in the polymer or polymer moiety.

[0176] Therefore, in a polymer portion containing "x" monomer units, any integer represented as "x" corresponds to the arithmetic mean of the monomers. Any range of integers represented as "x" provides a range of integers in which the arithmetic mean of the monomers lies. An integer "x" represented as "about x" means that the arithmetic mean of the monomers lies within the range of integers x+ / -10%, in a particular embodiment within the range of integers x+ / -8%, in a particular embodiment within the range of integers x+ / -5%, and in a particular embodiment within the range of integers x+ / -2%.

[0177] As used herein, the term “PEG-based” with respect to a portion or reagent means that the portion or reagent contains PEG. In certain embodiments, the PEG-based portion or reagent contains at least 10% (w / w) PEG, e.g., at least 20% (w / w) PEG, e.g., at least 30% (w / w) PEG, e.g., at least 40% (w / w) PEG, e.g., at least 50% (w / w), e.g., at least 60% (w / w) PEG, e.g., at least 70% (w / w) PEG, e.g., at least 80% (w / w) PEG, e.g., at least 90% (w / w) PEG, e.g., at least 95% (w / w) PEG. The remaining weight percentage of the PEG-based portion or reagent is other portions selected from the following portions and conjugates. - C 1-50 Alkyl, C 2-50 Alkenyl, C 2-50 Alkynyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl; and - The group comprising the following:

Chemical formula

[0178] As used herein, the term "PEG-based containing at least X% PEG" with respect to a portion or reagent means that the portion or reagent contains at least X% (w / w) ethylene glycol units (-CH2CH2O-), where the ethylene glycol units may be arranged alternately in blocks or randomly distributed within the portion or reagent. In certain embodiments, all of the ethylene glycol units of the portion or reagent are present in one block, and the remaining weight percentage of the PEG-based portion or reagent is, in certain embodiments, other portions selected from the following portions and bonds. - C 1-50 Alkyl, C 2-50 Alkenyl, C 2-50 Alkynyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclic, phenyl, naphthyl, indenyl, indanyl and tetralinyl, and - The group comprising the following:

Chemical formula

[0179] The term "hyaluronic acid system containing at least X% hyaluronic acid" as used herein is used as appropriate.

[0180] As used herein, the term “prodrug” refers to a drug moiety, such as a CNP moiety, that is reversibly and covalently conjugated to a polymer moiety, such as -Z, via a reversible linker moiety. A prodrug releases the reversibly and covalently conjugated drug moiety in the form of its corresponding drug. In other words, a prodrug is a conjugate comprising a drug moiety, such as a CNP moiety, that is covalently and reversibly conjugated to a polymer moiety via a reversible linker moiety, and the covalent and reversible conjugation of the polymer moiety to the reversible linker moiety is either direct or via a spacer. Such a prodrug or conjugate releases the previously conjugated drug moiety in the form of a free drug.

[0181] As used herein, the term “random coil” refers to a peptide or protein that, in certain embodiments, adopts / has / forms a three-dimensional structure substantially lacking distinct secondary and tertiary structures, as determined by circular dichroism spectroscopy performed in an aqueous buffer at ambient temperature and pH 7.4. In certain embodiments, the ambient temperature is approximately 20°C, i.e., 18°C ​​to 22°C, while in certain embodiments, the ambient temperature is 20°C.

[0182] As used herein, the term "reversible bond" refers to a bond that can be cleaved in the absence of an enzyme under physiological conditions (aqueous buffer at pH 7.4, 37 °C) and has a half-life of from 1 hour to 6 months, for example from 1 hour to 4 months, for example from 1 hour to 3 months, from 1 hour to 2 months, or from 1 hour to 1 month. Thus, a stable bond is a bond that has a half-life of greater than 6 months under physiological conditions (aqueous buffer at pH 7.4, 37 °C).

[0183] As used herein, the term "reagent" means a compound containing at least one functional group for reaction with a functional group of another compound or drug. It is understood that drugs containing functional groups (e.g., primary or secondary amines or hydroxyl functional groups) are also reagents.

[0184] As used herein, the term "reversible linker moiety" is a moiety that is covalently conjugated to a drug moiety such as a CNP moiety via a reversible bond and is also covalently conjugated to a polymer moiety such as -Z, wherein the covalent conjugation to the polymer moiety is either direct or via a spacer moiety such as -L 2 - etc. In certain embodiments, the bond between -Z and -L 2 - is a stable bond. A conjugate containing a reversible linker moiety can be referred to as a reversible conjugate.

[0185] As used herein, the term "spacer" or "spacer moiety" refers to a moiety suitable for linking two moieties together. Suitable spacers can be selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl or C 2-50 alkynyl, and this C 1-50 alkyl, C 2-50 alkenyl or C 2-50 alkynyl may optionally contain -NH-, -N(C 1-4 alkyl)-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)N(C 1-4One or more groups selected from alkyl)-, -OC(O)-, -S(O)-, -S(O)2-, 4- to 7-membered heterocyclyl, phenyl, and naphthyl are interposed.

[0186] As used herein, the term “substituted” means that one or more -H atoms of a molecule or part are substituted by a different atom or group of atoms called a “substituent.”

[0187] In certain embodiments, one or more such substituents are, independently of each other, halogen, -CN, -COOR x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; where -T 0 , C 1-50 Alkyl, C2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R x2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- may have one or more groups selected from the group consisting of these groups interspersed; -R x1 ,-R x1a ,-R x1b -H, -T are independent of each other. 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; where -T 0 , C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R x2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl has -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-;-S(O)2-,-S(O)-,-N(R x3 )S(O)2N(R x3a )-, -S-, -N(Rx3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- may have one or more groups selected from the group consisting of these groups interspersed; Each T 0 Phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Independently selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls; where each T 0 These are independently, identical or different, one or more -R x2 It is sometimes replaced by; Each-R x2 These are, independently, halogen, -CN, oxo (=O), and -COOR. x4 , -OR x4 , -C(O)R x4 ,-C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 ,-S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6Selected from the group consisting of alkyl groups; where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens; Each-R x3 ,-R x3a ,-R x4 ,-R x4a ,-R x4b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups; where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens.

[0188] In certain embodiments, the one or more substituents are, independently of each other, halogen, -CN, and -COOR x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(R x1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10Selected from the group consisting of alkynnyls; where -T 0 , C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is one or more identical or different -R x2 In some cases, it is replaced by C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl has -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(R x3 )- may have one or more groups selected from the group consisting of these groups interspersed; Each-R x1 ,-R x1a ,-R x1b ,-R x3 ,-R x3a These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls; where each T 0 These are independently, identical or different, one or more -R x2 It is sometimes replaced by; Each-R x2 These are, independently, halogen, -CN, oxo (=O), and -COOR. x4 , -OR x4 , -C(O)Rx4 ,-C(O)N(R x4 R x4a ), -S(O)2N(R x4 R x4a ), -S(O)N(R x4 R x4a ), -S(O)2R x4 ,-S(O)R x4 , -N(R x4 )S(O)2N(R x4a R x4b ), -SR x4 , -N(R x4 R x4a ), -NO2, -OC(O)R x4 , -N(R x4 )C(O)R x4a , -N(R x4 )S(O)2R x4a , -N(R x4 )S(O)R x4a , -N(R x4 )C(O)OR x4a , -N(R x4 )C(O)N(R x4a R x4b ), -OC(O)N(R x4 R x4a ), and C 1-6 Selected from the group consisting of alkyl groups; where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens; Each-R x4 ,-R x4a ,-R x4b These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls.

[0189] In certain embodiments, the one or more substituents are, independently of each other, halogen, -CN, and -COOR x1 , -OR x1 , -C(O)R x1 ,-C(O)N(R x1 R x1a ), -S(O)2N(R x1 R x1a ), -S(O)N(Rx1 R x1a ), -S(O)2R x1 ,-S(O)R x1 , -N(R x1 )S(O)2N(R x1a R x1b ), -SR x1 , -N(R x1 R x1a ), -NO2, -OC(O)R x1 , -N(R x1 )C(O)R x1a , -N(R x1 )S(O)2R x1a , -N(R x1 )S(O)R x1a , -N(R x1 )C(O)OR x1a , -N(R x1 )C(O)N(R x1a R x1b ), -OC(O)N(R x1 R x1a ), -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkynnyls; where -T 0 , C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl is one or more identical or different -R x2 In some cases, it is replaced by C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl has -T 0 -, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-,-S(O)2N(R x3 )-,-S(O)N(R x3 )-, -S(O)2-, -S(O)-, -N(R x3 )S(O)2N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a )-,-N(R x3 )C(O)N(R x3a )-, and -OC(O)N(Rx3 )- may have one or more groups selected from the group consisting of these groups interspersed; Each-R x1 ,-R x1a ,-R x1b ,-R x2 ,-R x3 ,-R x3a These are independently -H, halogen, and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; Each T 0 These are independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, and 8-11 membered heterobicyclyls; where each T 0 These are independently, identical or different, one or more -R x2 It is sometimes replaced.

[0190] In certain embodiments, up to six -H atoms in the optionally substituted molecule are independently substituted by substituents, for example, five -H atoms are independently substituted by substituents, four -H atoms are independently substituted by substituents, three -H atoms are independently substituted by substituents, two -H atoms are independently substituted by substituents, or one -H atom is independently substituted by substituents.

[0191] As used herein, the term “therapeutic dose” means an amount sufficient to cure, alleviate, or partially suppress the clinical symptoms of a given disease and its complications. The effective dose for each purpose is determined by the severity of the disease or injury in question, as well as body weight and overall health. Determining an appropriate dose can be achieved using routine experimentation by constructing a matrix of values ​​and testing the different points in that matrix, all of which is understood to be within the normal skill of a skilled physician. Within the scope of the present invention, therapeutic doses relate to doses aimed at achieving a therapeutic effect over a long period, i.e., at least one day, e.g., two days, e.g., three days, e.g., four days, e.g., five days, e.g., six days, e.g., one week, or e.g., two weeks.

[0192] As used herein, the term “traceless linker” refers to a reversible linker that, when cut, releases the drug in its free form.

[0193] As used herein, the term "water-soluble" with respect to a polymer portion means that, if such a polymer portion is part of a CNP conjugate, at least 1 g of the CNP conjugate containing such water-soluble polymer portion can be dissolved in 1 liter of water at 20°C to form a homogeneous solution.

[0194] Generally, the terms "comprise" or "comprising" also encompass "consist of" or "consisting of."

[0195] The amino acid sequence of a CNP polypeptide can be altered without significantly affecting the structure or function of the peptide. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to principles known in the art so as to have little effect on activity. For example, guidance on methods for producing phenotypically silent amino acid substitutions is provided in Bowie et al. (1990), Science 247:1306-1310, which is incorporated herein by reference in its entirety, in which the authors show that there are two main approaches to investigating the tolerance of amino acid sequences to alteration.

[0196] As used herein, the term "CNP analog" refers to a CNP from a different, unrelated organism that performs the same function in each organism but does not originate from an ancestral structure common to the ancestors of those organisms. Instead, the analog CNPs arose separately and subsequently evolved to perform the same or similar functions. In other words, analog CNP polypeptides are polypeptides with very different amino acid sequences that achieve the same biological activity, namely, the regulation of chondrocyte growth, proliferation, and differentiation in the chondrocytes of the chondrocyte growth plate.

[0197] As used herein, the term "CNP ortholog" refers to CNPs present in two different species whose sequences are related to one another via common homologous CNPs in the ancestral species, but which have evolved to be distinct from one another.

[0198] As used herein, the term "CNP homolog" refers to a CNP from a different organism that performs the same function in that organism and originates from an ancestral structure common to the ancestors of those organisms. In other words, a homologous CNP polypeptide is a polypeptide having a very similar amino acid sequence that achieves the same biological activity, namely, the regulation of the growth, proliferation, and differentiation of chondrocytes in the chondrogenic plate. In certain embodiments, a CNP polypeptide homolog may be defined as a polypeptide that exhibits at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% identity with respect to a reference CNP polypeptide.

[0199] Detailed description of the invention The present invention relates to a method for improving muscle function, such as skeletal muscle function, in a subject suffering from a disease or condition that impairs muscle function, wherein the method comprises the step of administering to the subject an effective amount of an FGFR3 signaling inhibitor, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist.

[0200] FGFR3 signaling inhibitors The FGFR3 signaling pathway is well understood and involves the MAPK and STET pathways. In non-pathological states, the receptor is activated by ligand (e.g., FGF1, FGF2, or FGF9) binding and receptor dimerization, where the tyrosine kinase domains of each member of the receptor dimer pair proximally meet and cross-phosphorylate each other on the tyrosine of the activation loop. This activates the kinase, which then binds to the adapter protein, phosphorylating the cytoplasm and triggering a downstream signaling cascade that controls cell proliferation and differentiation. Certain pathological conditions are associated with constitutive FGFR3 activation, in which receptor dimerization and phosphorylation can occur even without ligand binding.

[0201] Inhibition of FGFR3 signaling can occur by reducing or preventing the activity of the cascade at any point in the signaling cascade. For example, FGFR3 antagonists can bind to the receptor itself to reduce or prevent the binding of the activating ligand, and such molecules are directly defined as FGFR3 antagonists. Examples include anti-FGFR3 antibodies, such as FGFR3 monoclonal antibodies. A preferred example is disclosed in WO2022 / 040560, which discloses anti-FGFR3 monoclonal antibodies and their use in the treatment of chondrodysplasia, and is incorporated herein by reference in its entirety. Similarly, WO2018 / 145120 and WO2020 / 180898 disclose anti-FGFR3 monoclonal antibodies and their use in therapy, and are incorporated herein by reference in their entirety. Bofatamab (B-701) is a fibroblast growth factor receptor 3-specific monoclonal antibody currently in clinical development.

[0202] FGFR3 signaling inhibitors can also act to prevent FGFR3 signaling by preventing or reducing ligand binding to FGFR3. For this purpose, decoy molecules of FGFR3 ligands have been developed. By providing an alternative molecule to which the ligand can bind, signaling mediated by the FGFR3 molecule is reduced or inhibited. An example of a molecule that has been used to prevent excessive intracellular signaling mediated by FGFR3 and to rescue symptoms of chondrodysplasia is the soluble form of human FGFR3 (sFGFR3). It has been shown to act as a decoy receptor, preventing FGF from binding to FGFR3. FGFR3 soluble decoy / sFGFR3 polypeptides are disclosed in WO2016 / 110786, WO2022 / 106976 and WO2018 / 007597, all of which are incorporated herein by reference. Recifercept is an FGFR3-soluble decoy currently in clinical development for the treatment of chondrodysplasia in children (Goncalves et al., PLoS One. 2020;15(12):e0244368).

[0203] FGFR3 signaling inhibitors can also act to reduce or prevent FGFR3 signaling by acting on the intracellular portion of the FGFR3 molecule itself (e.g., by binding or otherwise preventing its activity) by preventing or reducing the phosphorylation of the FGFR3 molecule, for example. Tyrosine kinase inhibitors, such as infiglatinib or TYR300, an FGFR3 selective tyrosine kinase inhibitor, can be used for this purpose. WO2022 / 187443 discloses an FGFR3 selective FGFR3 inhibitor (tyrosine kinase inhibitor) for use in the treatment of chondrodysplasia and other disorders, which is incorporated herein by reference in its entirety. LY3866288, also known as LOXO-435 (or LOX-24350), is an FGFR3 inhibitor in clinical development.

[0204] Alternatively, FGFR3 signaling inhibitors may perform this function by acting on molecules downstream of the receptor in one or more of their signaling pathways (e.g., by binding to the molecule or preventing its activity). Such FGFR3 signaling pathway inhibitors can act to reduce or prevent the activity of the MAPK or STAT signaling pathways downstream of FGFR3. Examples of targets for FGFR3 signaling inhibitors in the MAPK pathway include the proteins ras, raf, mek, and erk. CNP thus acts as an inhibitor of the FGFR3 signaling pathway. Activation of the CNP receptor NPR-B leads to cGMP production and PKG activation, inhibiting raf kinase. Therefore, CNP and other NPR-B agonists can also be FGFR3 signaling inhibitors. Thus, FGFR3 signaling inhibitors can act directly or indirectly on FGFR3 itself, ras, raf, mek, and erk, or one or more of STAT.

[0205] Similarly, preventing or reducing the expression of the FGFR3 protein itself is another possible way to inhibit FGFR3 signaling. Therefore, FGFR3 signaling inhibitors can act to reduce or decrease the amount of FGFR3 protein in cells. Examples of appropriate strategies include antisense molecules and siRNAs directed at the FGFR3 protein itself. In such cases, the amount of FGFR3 in the relevant cell may be less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the amount of FGFR3 in the cell in the absence of the siRNA or antisense molecule, or before the administration of the siRNA or antisense molecule.

[0206] Therefore, preferred examples of FGFR3 signaling inhibitors include antibodies against FGFR3 (e.g., antagonist antibodies against FGFR3), tyrosine kinase inhibitors (e.g., infiglatinib, pemigatinib, futovatinib, erdafitinib, or TYRA-300), molecules that prevent or reduce FGFR3-ligand binding, molecules that inhibit FGFR3 signaling via NPR-B receptor activation (e.g., type C natriuretic peptide (CNP) and its variants), FGFR3 siRNAs, and FGFR3 antisense oligonucleotides.

[0207] In certain embodiments, the fibroblast growth factor receptor 3 (FGFR3) antagonist is infigratinib having the following structure, or a pharmaceutically acceptable salt thereof: [ka]

[0208] Infigratinib is approved for the treatment of certain cancers and is currently in clinical development for the treatment of chondrodysplasia in children aged 3 to 11 years, administered in tablet form at a maximum dose of 0.25 mg / kg per day. High doses of infigratinib used for cancer treatment can cause side effects including muscle weakness and muscle cramps; therefore, in the context of this invention, it is desirable to limit the daily dose to approximately 3 mg / kg or less, for example, approximately 0.25 mg / kg or less.

[0209] Other FGFR3 signaling inhibitors include pemigatinib, futivatinib, erdafitinib, or TYRA-300. FGFR3 signaling inhibitors, including TYRA-300, are disclosed in WO2023 / 279041, WO2021 / 138392, WO2022 / 147246, and WO2021 / 138391, which are incorporated herein by reference in their entirety.

[0210] FGFR3 signaling inhibitors can be identified and characterized by standard methods, such as those described in WO2023 / 279041, WO2021 / 138392, WO2022 / 147246 and WO2021 / 138391.

[0211] CNP drug In advantageous embodiments, C-type natriuretic peptide (CNP) drugs are used. As discussed above, in vivo CNP binds to NPR-B and exerts its effect on the FGFR3 signaling pathway, and therefore can also be described as an NPR-B agonist. Other NPR-B agonists, including small molecule NPR-B receptor agonists, can also be used according to the present invention.

[0212] A CNP drug is a molecule containing the CNP peptide as defined above. The CNP drug and CNP peptide are preferably administered in the form of an NPR-B agonist as defined above, or in a form that produces an NPR-B agonist in vivo (for example, as a result of an in vivo treatment that releases a CNP peptide that is an NPR-B agonist in vivo).

[0213] For example, CNP drugs can be administered in the form of CNP peptides, CNP peptide conjugates, or CNP prodrugs. The method of the present invention may also employ NPR-C ligands; CNP is an example of an NPR-C ligand.

[0214] FGFR3 inhibition assay Guagnana et al., J. Med. Chem. 2011, 54, 7066-7083, which is incorporated herein by reference in its entirety, provides a radiokinase assay that can be used to identify FGFR3 tyrosine kinase inhibitors: enzyme kinase activity measures the phosphorylation of a synthetic substrate by a purified GST-fused FGFR3-K650E kinase domain in the presence of radiolabeled ATP. Also disclosed by Guagnana et al. are a BaF3 cell line proliferation assay and an FGFR1-4 cell autophosphorylation assay, which can also be used to identify FGFR3 inhibitors.

[0215] NPR-B activity assays can be used to identify NPR-B agonists. Functional CNP peptides, free CNP released from CNP prodrugs, and other NPR-B agonists are identified using NPR-B assays, such as the one reported in Breinholt et al., 2019 J Pharmacol Exp Ther 370:459-471, which is incorporated herein by reference in its entirety.

[0216] The activity of CNPs that induce the intracellular cyclic guanosine monophosphate (cGMP) response can be determined in NIH3T3 cells. These cells express NPR-B on their cell surface (Abbey and Potter, 2003 Endocrinology, Volume 144, Issue 1, 1 January 2003, Pages 240-246), and stimulation of this receptor with CNPs induces intracellular production of cGMP, a secondary messenger. Briefly, NIH3T3 cells are cultured at 37°C and 5% CO2 in Dulbecco's modified Eagle medium F-12 supplemented with 5% FBS and 5 mM glutamine. In each assay, cells are resuspended in a stimulant buffer (Dulbecco's PBS containing 0.5 mM 3-isobutyl-1-methylxanthine) and seeded in 96-well plates (5 × 10⁶). 4The cells were double-incubated with different concentrations of CNP ( / well). After incubation at 37°C and 5% CO2 for 30 minutes, the cells were lysed with the supplied lysis buffer, and cGMP levels were measured using a commercially available cGMP assay based on time-resolved fluorescence energy transfer (cGMP kit, catalog 62GM2PEB; Cisbio, Codolet, France). Activity was determined by parallel line analysis of the sample compared to CNP-38 (SEQ ID NO: 24(CNP-38): LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, where cysteine ​​at positions 22 and 38 are linked by disulfide crosslinks) using a 4-parameter logistic curve fit (PLA 2.0 software; Stegmann Systems, Rodgau, Germany).

[0217] In certain embodiments, an NPR-B agonist (e.g., type C natriuretic peptide) exhibits at least about 25% of the NPR-B activity of the CNP-38 reference standard (activity that induces an intracellular cGMP response in the NIH3T3 cell assay), for example, at least about 50%, 75%, 80%, 85%, or 90% of the activity of the CNP-38 reference standard, in the NPR-B activity assay described above.

[0218] In the case of CNP prodrugs, it is understood that the activity of the prodrug in a CNP assay needs to be evaluated using the CNP released from the prodrug (free CNP).

[0219] NPR-C affinity and agonist assays that can be used to identify NPR-C agonists Functional CNP peptides, free CNP released from CNP prodrugs, and other NPR-C ligands can be identified using NPR-C affinity assays, such as the one reported in Breinholt et al., 2019 J Pharmacol Exp Ther 370:459-471.

[0220] This NPR-C affinity assay uses the HEK293 cell line, which stably overexpresses human NPR-C. This NPR-C affinity assay can be used to evaluate the relative NPR-C affinity of CNP or another NPR-C ligand to a CNP-38 standard. In certain embodiments, the type C natriuretic peptide has at least about 25% of the NPR-C affinity of the CNP-38 reference standard in the NPR-C affinity assay, for example, at least about 50% of the affinity of the CNP-38 reference standard for NPR-C, for example, at least about 75% of the affinity of the CNP-38 reference standard for NPR-C.

[0221] Zhou and Murthy, Am J Physiol Cell Physiol 284:C1255-C1261, 2003, which is incorporated herein by reference in its entirety, reports on the G protein activating activity of NPRC and provides an assay for identifying receptor-activating G proteins by [35S]GTPγS binding assay and an assay for PLC-beta activity, both of which can be used to identify NPR-C ligands having NPR-C agonist activity (NPR-C agonists: for example, the standard used when evaluating NPR-C agonists in an NPR-C activity assay is cANP4-23). ​​Zhou and Murthy further disclose a [125I]ANP binding assay that can be used to identify NPR-C ligands.

[0222] Exemplary CNP (including CNP peptides) Naturally occurring human CNP-22 (SEQ ID NO: 1) has the following sequence: GLSKGCFGLKLDRIGSMSGLGC Here, the cysteine ​​molecules at positions 6 and 22 are linked by disulfide bridges.

[0223] In certain embodiments, the term "CNP" also refers to the following peptide sequence: Sequence ID 2 (CNP-53): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 3 (G-CNP-53): GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 4 (M-CNP-53): MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 5 (P-CNP-53): PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 6 (CNP-53 M48N): DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 7 (CNP-53 Δ15-31): DLRVDTKSRAAWARGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 8 (CNP-52): LRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 9 (CNP-51): RVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 10 (CNP-50): VDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 11 (CNP-49): DTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 12 (CNP-48): TKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 13 (CNP-47): KSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 14 (CNP-46): SRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 15 (CNP-45): RAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 16 (CNP-44): AAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 17 (CNP-44 Δ14-22): AAWARLLQEHPNAGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 18 (CNP-44 Δ15-22): AAWARLLQEHPNARGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 19 (CNP-43): AWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 20 (CNP-42): WARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 21 (CNP-41): ARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 22 (CNP-40): RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 23 (CNP-39): LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 24 (CNP-38): LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, Here, the cysteine ​​molecules at positions 22 and 38 are linked by disulfide bridges. Sequence ID 25 (CNP-37): QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 26 (CNP-37 Q1pQ, where pQ = pyroglutamic acid): pQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 27 (G-CNP-37): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 28 (P-CNP-37): PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 29 (M-CNP-37): MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 30 (PG-CNP-37) (bosolitide peptide sequence): PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 31 (MG-CNP-37): MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 32 (CNP-37 M32N): QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 33 (G-CNP-37 M32N): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 34 (G-CNP-37 K14Q): GQEHPNARKYKGANQKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 35 (G-CNP-37 K14P): GQEHPNARKYKGANPKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 36 (G-CNP-37 K14Q, Δ15): GQEHPNARKYKGANQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 37 (G-CNP-37 K14Q, K15Q): GQEHPNARKYKGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 38 (CNP-36): EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 39 (CNP-35): HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 40 (CNP-34): PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 41 (CNP-33): NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 42 (CNP-32): ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 43 (CNP-31): RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 44 (CNP-30): KYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 45 (CNP-29): YKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 46 (CNP-28): KGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 47 (GHKSEVAHRF-CNP-28): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 48 (CNP-27): GANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 49 (CNP-27 K4Q, K5Q): GANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 50 (CNP-27 K4R, K5R): GANRRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 51 (CNP-27 K4P, K5R): GANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 52 (CNP-27 K4S, K5S): GANSSGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 53 (CNP-27 K4P, K5R): GANGANPRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 54 (CNP-27 K4R, K5R, K9R): GANRRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 55 (CNP-27 K4R, K5R, K9R, M22N): GANRRGLSRGCFGLKLDRIGSNSGLGC; Sequence ID 56 (P-CNP-27 K4R, K5R, K9R): PGANRRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 57 (M-CNP-27 K4R, K5R, K9R): MGANRRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 58 (HSA fragment-CNP-27): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLG; Sequence ID 59 (HSA fragment-CNP-27 M22N): GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSNSGLGC; Sequence ID 60 (M-HSA fragment-CNP-27): MGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 61 (P-HSA fragment-CNP-27): PGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 62 (CNP-26): ANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 63 (CNP-25): NKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 64 (CNP-24): KKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 65 (CNP-23): KGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 66 (R-CNP-22): RGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 67 (ER-CNP-22): ERGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 68 (R-CNP-22 K4R): RGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 69 (ER-CNP-22 4KR): ERGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 70 (RR-CNP-22): RRGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 71 (HRGP fragment-CNP-22): GHHSHEQHPHGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 72 (HRGP fragment-CNP-22): GAHHPHEHDTHGANQQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 73 (HRGP fragment-CNP-22): GHHSHEQHPHGANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 74 (IgG1(F c ) fragment-CNP-22): GQPREPQVYTLPSGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 75 (HSA fragment-CNP-22): GQHKDDNPNLPRGANPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 76 (HSA fragment-CNP-22): GERAFKAWAVARLSQGLSKGCFGLKLDRIGSMSGLGC; Sequence ID No. 77 (Osteoclinic NPR C inhibitor fragment - CNP22): FGIPMDRIGRNPRGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 78 (FGF2 heparin-binding domain fragment - CNP22): GKRTGQYKLGSKTGPGPKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 79 (IgG1(F c (Fragment - CNP-22 K4R): GQPREPQVYTGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 80 (HSA fragment-CNP-22 K4R): GVPQVSTSTGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 81 (Fibronectin fragment-CNP-22 K4R): GQPSSSSQSTGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 82 (Fibronectin fragment-CNP-22 K4R): GQTHSSGTQSGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 83 (Fibronectin fragment-CNP-22 K4R): GSTGQWHSESGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 84 (Zinc finger fragment-CNP-22 K4R): GSSSSSSSSSGANQQGLSRGCFGLKLDRIGSMSGLGC; Sequence ID 85 (CNP-21): LSKGCFGLKLDRIGSMSGLGC; Sequence ID 86 (CNP-20): SKGCFGLKLDRIGSMSGLGC; Sequence ID 87 (CNP-19): KGCFGLKLDRIGSMSGLGC; Sequence ID 88 (CNP-18): GCFGLKLDRIGSMSGLGC; Sequence ID 89 (CNP-17): CFGLKLDRIGSMSGLGC; Sequence ID 90 (BNP fragment-CNP-17-BNP fragment): SPKMVQGSGCFGLKLDRIGSMSGLGCKVLRRH; Sequence ID 91 (CNP-38 L1G): GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 92 (Ac-CNP-37; where Ac = acetyl): Ac-QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; Sequence ID 93: QEHPNARX1YX2GANX3X4GLSX5GCFGLX6LDRIGSMSGLGC, Here, X1, X2, X3, X4, X5, and X6 are independently selected from the group consisting of K, R, P, S, and Q, provided that at least one of X1, X2, X3, X4, X5, and X6 is selected from the group consisting of R, P, S, and Q; in a particular embodiment, X1, X2, X3, X4, X5, and X6 are selected from the group consisting of K and R, provided that at least one of X1, X2, X3, X4, X5, and X6 is R; Sequence ID 94: QEHPNARKYKGANX1X2GLSX3GCFGLX4LDRIGSMSGLGC, Here, X1, X2, X3, and X4 are independently selected from the group consisting of K, R, P, S, and Q, provided that at least one of X1, X2, X3, and X4 is selected from the group consisting of R, P, S, and Q; in a particular embodiment, X1, X2, X3, and X4 are selected from K and R, provided that at least one of X1, X2, X3, and X4 is R; Sequence ID 95: QEHPNARKYKGANX1X2GLSKGCFGLKLDRIGSMSGLGC, Here, X1X2 is selected from the group consisting of KR, RK, KP, PK, SS, RS, SR, QK, QR, KQ, RQ, RR, and QQ.

[0224] In sequence numbers 2 through 95, it can be seen that the cysteine ​​equivalents at positions 22 and 38 of sequence number 24 are linked by disulfide bridges.

[0225] Those skilled in the art are also aware that the conjugate of the present invention may be a prodrug.

[0226] The unit dose contained in the unit dosage form of the present invention is determined by the patient's actual body weight.

[0227] Bosolitide is approved for once-daily subcutaneous administration at a dose of 15 μg / kg or approximately 15 μg / kg, although higher doses (e.g., approximately 30 μg / kg) may be administered to infants. Bosolitide is currently available in 0.4 mg, 0.56 mg, and 1.2 mg vials, and the current recommended daily doses based on actual body weight (ABW) are as follows: 10-11kg: 0.24mg SC qDay 12-16kg: 0.28mg SC qDay 17-21kg: 0.32mg SC qDay 22-32kg: 0.4mg SC qDay 33-43kg: 0.5mg SC qDay 44-59kg: 0.6mg SC qDay 60-89kg: 0.7mg SC qDay ≧90kg or more: 0.8mg SC qDay Higher doses have been reported to be more effective in younger children.

[0228] In certain embodiments, the unit dose is 50 μg to 7000 μg of CNP. In certain embodiments, the unit dose is 100 μg to 5000 μg of CNP. In certain embodiments, the unit dose is 100 μg to 3000 μg of CNP. In certain embodiments, the unit dose is 100 μg to 2000 μg of CNP. In certain embodiments, the unit dose is 100 μg to 1000 μg of CNP. In certain embodiments, the unit dose is 150 μg to 750 μg of CNP. In certain embodiments, the unit dose is 150 μg to 500 μg of CNP. In certain embodiments, the unit dose is 150 μg to 350 μg of CNP. In certain embodiments, the unit dose is approximately 700 μg of CNP. In certain embodiments, the unit dose is approximately 600 μg of CNP. In certain embodiments, the unit dose is approximately 500 μg of CNP. In certain embodiments, the unit dose is approximately 400 μg CNP. In certain embodiments, the unit dose is approximately 300 μg CNP.

[0229] In certain embodiments, the unit dose is approximately 6 μg CNP / kg. In certain embodiments, the unit dose is approximately 20 μg CNP / kg. In certain embodiments, the unit dose is approximately 50 μg CNP / kg. In certain embodiments, the unit dose is approximately 75 μg CNP / kg. In certain embodiments, the unit dose is approximately 100 μg CNP / kg. In certain embodiments, the unit dose is approximately 125 μg CNP / kg. In certain embodiments, the unit dose is approximately 150 μg CNP / kg.

[0230] In certain embodiments, the unit dose is 6 μg CNP / kg. In certain embodiments, the unit dose is 20 μg CNP / kg. In certain embodiments, the unit dose is 50 μg CNP / kg. In certain embodiments, the unit dose is 75 μg CNP / kg. In certain embodiments, the unit dose is 100 μg CNP / kg. In certain embodiments, the unit dose is 125 μg CNP / kg. In certain embodiments, the unit dose is 150 μg CNP / kg.

[0231] In certain embodiments, the unit dosage form is a liquid. In certain embodiments, the unit dosage form is a solid.

[0232] In certain embodiments, for example, the compound of formula (IIf') or formula (IIf) or compound (1), the unit dose is in the range of approximately 12.3 nmol CNP / kg to at least approximately 37 nmol CNP / kg. In certain embodiments, the unit dose is 12.3 nmol CNP / kg to 36.9 nmol CNP / kg. In certain embodiments, the unit dose is at least 24.6 nmol CNP / kg. In certain embodiments, the unit dose is approximately 24.6 nmol CNP / kg. In certain embodiments, the unit dose is 24.6 nmol CNP / kg.

[0233] In certain embodiments, for example, the compound of formula (IIf') or formula (IIf) or compound (1), the unit dose is in the range of approximately 6 μg CNP / kg to at least approximately 100 μg CNP / kg. In certain embodiments, the unit dose is approximately 6 μg CNP / kg to approximately 150 μg CNP / kg.

[0234] In certain embodiments, for example, with respect to formula (IIf') or formula (IIf) or compound (1), the unit dose contained in the unit dosage form of the present invention is 6 μg CNP / kg to at least 100 μg CNP / kg. In certain embodiments, the unit dose is 6 μg CNP / kg to 150 μg CNP / kg.

[0235] The unit dose is preferably administered once a week.

[0236] In the case of a CNP conjugate or CNP prodrug, for example, a compound of formula (IIf') or formula (IIf) or compound (1), "x" μg CNP / kg is understood to mean "x" μg of CNP per kg of patient body weight, i.e., the CNP portion contained within the CNP conjugate. Similarly, "y" nmol CNP / kg is understood to mean "y" nmol of CNP per kilogram of patient body weight, i.e., "y" nmol of the CNP portion contained within the CNP conjugate.

[0237] Target / Patients In certain embodiments, the subjects are adults. Adult humans are 18 years of age or older. In certain embodiments, the subjects are at least 19 years of age, for example, at least 20 or 25 years of age.

[0238] In certain embodiments, the subjects are pediatric patients, i.e., under 18 years of age, for example, under 16 or under 14 years of age, or 5 years of age. In certain embodiments, the subjects are infants (for example, under 1 year of age, or under 9 or 6 months of age).

[0239] The subject is also called a patient.

[0240] In certain embodiments, the patient's weight is approximately 2 kg to approximately 80 kg. In certain embodiments, the patient's weight is approximately 4 kg to approximately 60 kg. In certain embodiments, the patient's weight is approximately 5 kg. In certain embodiments, the patient's weight is approximately 9 kg. In certain embodiments, the patient's weight is approximately 10 kg. In certain embodiments, the patient's weight is approximately 11 kg. In certain embodiments, the patient's weight is approximately 12 kg. In certain embodiments, the patient's weight is approximately 15 kg. In certain embodiments, the patient's weight is approximately 20 kg. In certain embodiments, the patient's weight is (at least approximately) 30 kg. In certain embodiments, the patient's weight is (at least approximately) 40 kg. In certain embodiments, the patient's weight is (at least approximately) 50 kg. In certain embodiments, the patient's weight is (at least approximately) 60 kg. In certain embodiments, the patient's weight is (at least approximately) 70 kg. In certain embodiments, the patient's weight is (at least approximately) 80 kg.

[0241] Diseases or conditions that impair muscle function In certain embodiments, the subject suffers from a disease or condition that impairs muscle function (e.g., skeletal muscle). This means that normal muscle function is reduced or absent. The reduction in muscle function can be assessed against a threshold level or against an individual without the disease or condition. The loss or reduction of muscle function may result from a disease or condition that directly affects the muscles (e.g., myopathy), or from a disease that affects the neuromuscular junction or the nervous system.

[0242] Diseases or conditions that impair muscle function (e.g., skeletal muscle) may include chondrodysplasia, such as diseases selected from the group consisting of chondrodysplasia, hypochondrodysplasia, and lethal dysplasia of bone. In certain embodiments, the subject has chondrodysplasia.

[0243] In certain embodiments, the subject has RASopathy.

[0244] In certain embodiments, the subject has a disease selected from the group consisting of chondrodysplasia, such as chondrodysplasia, hypochondrodysplasia, and lethal dysplasia. In certain embodiments, the subject has chondrodysplasia.

[0245] In certain embodiments, the subjects do not have chondrodysplasia, for example, a disease selected from the group consisting of chondrodysplasia, hypochondroplasia, and lethal dysplasia. In certain embodiments, the subjects do not have chondrodysplasia. In certain embodiments, the subjects do not have chondrodysplasia.

[0246] Skeletal muscle is one of the three main types of muscle in the body, the other being cardiac muscle and smooth muscle. Skeletal muscle is muscle that attaches to bone via tendons. Skeletal muscle is also sometimes called striate muscle. Administration of FGFR3 signaling inhibitors, NPR-B agonists, or NPR-C agonists has been shown to improve muscle function, particularly skeletal muscle function.

[0247] In certain embodiments, the subject has myopathy. Myopathy is a heterogeneous group of disorders that primarily affect the structure, metabolism, or channel function of skeletal muscle, typically resulting in muscle weakness, stiffness, cramps, and spasms, and may cause or contribute to skeletal malformations, such as abnormal curvature of the spine. Myopathy usually presents with muscle weakness that interferes with daily activities. In some embodiments, the myopathy or muscle dysfunction may be mitochondrial myopathy, i.e., myopathy caused by a deficiency of mitochondria. Myopathy can be hereditary or acquired. Hereditary myopathy may be congenital myopathy, i.e., the symptoms of myopathy may begin at birth or in infancy.

[0248] In certain embodiments, the subject has a disease or condition related to impaired neuromuscular function, such as a neuromuscular disease or a neurodegenerative disease.

[0249] Therefore, in some embodiments, the method is performed on subjects with diseases or conditions related to impaired neuromuscular function, such as neuromuscular diseases or neurodegenerative diseases.

[0250] The present invention also provides a method for treating or preventing a disease or condition associated with impaired neuromuscular function, such as a neuromuscular disease or a neurodegenerative disease, wherein the method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist (e.g., an NPR-B agonist, e.g., a C-type natriuretic peptide (e.g., a CNP conjugate)) to a subject suffering from a neuromuscular disease or a neurodegenerative disease. In some embodiments, the neuromuscular disease or neurodegenerative disease is a disease in which mitochondrial dysfunction is present.

[0251] The administration of an effective dose of an FGFR3 signaling inhibitor, NPR-B agonist, or NPR-C agonist (e.g., an NPR-B agonist) to a subject having a disease or condition associated with impaired neuromuscular function may result in an improvement in mitochondrial function in the subject. This can be observed (or monitored), for example, through improved muscle function, e.g., improved skeletal muscle function or improved neuromuscular function; or through delayed, delayed, or reduced disease progression (e.g., compared to a reference subject, or a subject before treatment or without treatment), e.g., a reduced rate of loss or decline of muscle function, or a reduced rate of loss or decline of neuromuscular function. In some embodiments, the treatment method may be initiated after diagnosis of a disease or condition associated with impaired neuromuscular function, and optionally before significant or marked loss of muscle or neuromuscular function.

[0252] Mitochondrial dysfunction, or mitochondrial dysfunction, is noted in many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), ataxia, such as Friedreich's ataxia (FRDA), and amyotrophic lateral sclerosis (ALS). Mitochondrial dysfunction can be identified by the diagnosis of diseases or disorders associated with mitochondrial dysfunction, through genetic testing, i.e., identification of gene polymorphisms associated with or causing mitochondrial dysfunction, through biochemical analysis from biopsies of affected tissue, or through biochemical markers in blood or urine (see, for example, Muraresku et al., Curr Genet Med Rep. 2018 Jun;6(2):62-72).

[0253] Diseases or conditions associated with impaired neuromuscular function may include neuromuscular disorders / neuromuscular diseases (NMDs). Preferred NMD disorders and diseases may be associated with mitochondrial dysfunction and impairment (see, for example, Marra et al., Biomolecules 2021, vol 11 (11); 1633). Therefore, the methods of the present invention may be used to improve mitochondrial function or slow the decline of mitochondrial function (for example, compared to, or to, pre-treatment or untreated subjects) in subjects having diseases or conditions associated with impaired neuromuscular function (e.g., NMDs).

[0254] Therefore, the methods of the present invention can be used to improve muscle function or slow the decline of muscle function in these diseases or conditions associated with impaired neuromuscular function. Examples of neuromuscular diseases include muscular dystrophy and myopathy, as well as genetically acquired diseases including neuromuscular diseases. Neuromuscular diseases include neurodegenerative diseases and disorders associated with loss of mitochondrial function, and may be selected from the group consisting of, for example, motor neuron disease (MND, also known as amyotrophic lateral sclerosis (ALS)); Parkinson's disease (PD), multiple sclerosis (MS, including progressive MS or relapsing-remitting MS); Alzheimer's disease (AD); ataxia, such as Friedreich's ataxia (FRDA), and Huntington's disease (HD).

[0255] Parkinson's disease (PD) is associated with mitochondrial dysfunction, and the pathophysiology in PD leads to muscle weakness and fatigue (Borsche et al., J Parkinsons Dis. 2021;11(1):45-60). Timmer et al., J Neurosci. 2007 Jan 17;27(3):459-471 demonstrates abnormalities in FGFR3 / FGF-2 signaling in an animal model of PD. Central and systemic CNP (amino-terminal proCNP) levels are both reduced in Parkinson's disease and can be restored with treatment with monoamine oxidase inhibitors (Espiner et al., J Neural Transm (Vienna). 2014 Apr;121(4):371-8; Woodward, Parkinsonism Relat Disord. 2017 Oct;43:15-19). Muscle weakness and fatigue, which can significantly affect gait, are commonly reported by PD patients. Zheng et al., Sci Transl Med. 2010 Oct 6;2(52):52ra73, reported PGC-1α as a therapeutic target for Parkinson's disease. Mitochondrial dysfunction is a central dysfunction in the pathogenesis of Parkinson's disease (PD), and PD-related genes, including PGC-1α, are closely linked to mitochondrial integrity (Piccinin, Int. J. Mol. Sci 2001 22(7) 3487). Low expression of PGC-1α has been noted in PD, and there is a need for therapeutic agents that increase PGC-1α expression and enhance mitochondrial function in PD patients.

[0256] In PD patients, muscle function can be routinely monitored using physical function tests, such as sit-to-stand tests and 6-minute walk tests (see, e.g., Clael et al, Neurosci J 2918 8507018). Appropriate physical function tests used for monitoring PD patients include speech, facial expressions, standing up from a chair, walking, or postural stability (see, e.g., Brusse et al., Physical Therapy, Volume 85, Issue 2, 1 February 2005, Pages 134-141). Recently, the FDA approved a PD monitoring app (Rube Labs) for patient monitoring via smart devices (e.g., mobile phones or smartwatches), which can provide 24-hour monitoring of physical activity, such as walking, as well as other PD symptoms, such as tremors and dyskinesia. It is therefore anticipated that such smart device apps will be used to monitor effective treatment according to the present invention.

[0257] Decreased PGC-1α expression contributes to mitochondrial dysfunction and correlates with neuronal loss in multiple sclerosis (Witte et al., Acta Neuropathol. 2013 Feb;125(2):231-43;Peixoto de Barcelos Biology (Basel) 2019 8(2):37). Rosenkranz et al., eLife 2021;10:e61798 reported that enhancing mitochondrial activity in neurons prevents neurodegeneration in a multiple sclerosis (MS) model mouse, suggesting that enhancing mitochondrial activity in neurons could be a therapeutic strategy for MS. Rajendran et al., Cells 2021 reported on FGFR inhibition as a therapeutic option that reduces FGF / FGFR signaling and inflammation and induces remyelination in MS. Multiple sclerosis causes muscle fatigue, pain, imbalance, and decreased physical activity, and is also a contributing factor to muscle weakness. In fact, muscle fatigue is considered to be the most common symptom of MS. Monitoring muscle function in MS can be done using self-report questionnaires or smart devices, and remote monitoring of fatigue and activity can be provided (e.g., Block Front. Neurol. 2022 13 https: / / doi.org / 10.3389 / fneur.2022.878313, Stuart et al., Mult Scler J Exp Transl Clin. 2020 Dec 7;6(4):2055217320975185). Witte et al. reported that decreased PGC-1α expression correlates with neuronal loss in MS.

[0258] Zhao et al., Cells 2002 Jul;11(13) 2049, reported that mitochondrial dysfunction is an important contributing factor to amyotrophic lateral sclerosis (ALS) and is associated with and involved in the pathogenesis of the disease. Zhao et al., Molecular Neurodegeneration 6, Article number:51 (2011), reported that PGC-1α plays a protective role in ALS.

[0259] Impairment of mitochondrial biosynthesis mediated by PGC-1α has been noted in the pathogenesis of Alzheimer's disease and precedes mitochondrial dysfunction associated with the progression of AD (Bhatia, Curr. Neuropharmacol. 2002 20(4):675-692). In patients surviving dementia, such as Alzheimer's disease (AD), physical function is affected, leading to decreased reaction time, muscle weakness, impaired coordination, and impaired balance, which, along with cognitive impairment, are major causes of falls and fractures. In the later stages of dementia, physical ability declines significantly, and walking, gait, and movement may be severely restricted (see, for example, Taraldsen et al., BMC Geriatrics volume 21, Article number:670 (2021), which reports on the use of body accelerometer sensors to monitor the daily physical activity of dementia patients).

[0260] Administration of FGFR3 signaling inhibitors, NPR-B agonists, or NPR-C agonists may result in various changes in muscle function.

[0261] For example, muscle strength can improve. Muscle strength is the maximum ability to exert force in a short period of time. This can be assessed using, for example, the Oxford Scale. The Oxford Scale tests the major muscles of the upper and lower limbs against the examiner's resistance, and the patient's muscle strength is assessed on a scale of 0 to 5 accordingly (Naqvi U. Muscle strength grading. InStatpearls [Internet] 2019 May 29. StatPearls Publishing. Available from:https: / / www.ncbi.nlm.nih.gov / books / NBK436008 / ): • 0 No muscle activity • 1. Track muscle activity such as spasms without achieving the full range of motion. • 2. Activate muscles in a gravity-free environment to achieve full range of motion. • 3. Activation of muscles that resist gravity, full range of motion 4. Muscle activation in response to a certain degree of resistance, full range of motion • 5. Muscle activation relative to the examiner's total resistance and full range of motion.

[0262] The muscles commonly tested are the shoulder abductors, elbow flexors, elbow extensors, wrist extensors, finger flexors, wrist inversions, hip flexors, knee extensors, dorsiflexors, extensor hallucis, and plantar flexors. These muscle groups are generally selected to systematically assess important spinal nerve roots; for example, testing the strength of the elbow flexors, elbow extensors, wrist extensors, finger flexors, and intrinsic hand muscles allows for a systematic assessment of nerve roots from C5 to T1. Alternatively or additionally, distal muscle strength can be semi-quantitatively measured using a handgrip ergometer (or an inflated BP cuff gripped by the patient), recording grip strength, or dynamometry can be performed to more accurately measure the force the muscles can exert and record the difference in muscle strength over time. Therefore, an increase in muscle strength is observed as an increase in the Oxford score or an increase in distal muscle strength assessed by a handgrip ergometer (or an inflated BP cuff held by the patient) to record grip strength, or by dynamometry.

[0263] For example, muscle tone may improve. Muscle tone, also known as residual muscle tone or tone, is the resistance of a muscle to sustained and passive partial contraction or passive stretching at rest. Muscle tone helps maintain posture and decreases during REM sleep. Muscle tone is different from muscle strength. Muscle tone is regulated by the activity of motor neurons and can be affected by various factors such as age, disease, and nerve damage. Hypotonia refers to a decrease in resting muscle tone and reduced resistance to passive movement. Hypotonia rarely occurs alone without some degree of muscle weakness. Hypotonia (low muscle tone) refers to a state in which muscle rigidity is reduced, making it difficult to effectively maintain an upright posture against gravity or to exert appropriate force during contraction. As a result, hypotonia muscles tend to become more flexible rather than stiff. Hypotonia is observed in individuals with various conditions, such as Down syndrome, muscular dystrophy, cerebral palsy, Prader-Willi syndrome, myotonic dystrophy, Marfan syndrome, and Tay-Sachs disease. Hypotonia is generally assessed through medical observation, and improvement in hypotonia is accompanied by increased resting tension and resistance to passive movement, as assessed by medical professionals.

[0264] For example, there may be an improvement in muscular endurance (or muscular stamina). This is the resistance of a muscle or muscle group to fatigue during repetitive muscle contractions against external forces. This is usually assessed by observation, for example, by performing repetitive exercises over a period of time, such as counting the number of push-ups a patient can perform within a period of time, for example, 60 seconds, or by measuring the time it takes an individual to repeat a certain number of exercises. Improvement in muscular endurance manifests as an increase in the number of repetitions performed within a period of time, or a decrease in the time required to repeat a certain number of exercises.

[0265] For example, there may be an improvement in muscle mass. Muscle mass is the amount of muscle in the subject's body, including skeletal muscle, smooth muscle, and cardiac muscle. In a preferred embodiment, there may be an improvement in skeletal muscle mass. Muscle mass can be measured, for example, by performing dual-energy X-ray absorptiometry, CT scans, or MRI scans. Muscle mass can be increased by the methods of the present invention, and an increase in muscle mass may also result in an increase in the muscle-to-fat ratio (e.g., the skeletal muscle-to-fat ratio). Fat mass can be measured using DEXA and bioelectrical impedance analysis (BIA). Additionally or alternatively, one or more of the subject's muscle volume, muscle density, and muscle length may also increase.

[0266] For example, a reduction in muscle fatigue may occur. Muscle fatigue is used to describe a decrease in the force generated by a muscle or group of muscles during repetitive contractions in response to an external force. One example of a test to measure muscle fatigue is the Biering-Sorenson test, which has been used to assess fatigue in the trunk extensor muscles and is also used as a test for low back pain. The test, described by Sorenson (Biering-Sorensen F. Physical measurements as risk indicators for low-back trouble over a one-year period. Spine. 1984;9:106-119), involves "a subject lying face down with their buttocks and legs secured to a sofa with three wide canvas straps and their arms folded in front of their chest, and measuring how many seconds they can keep their unsupported upper body (from the upper edge of the iliac crest) horizontal." A reduction in muscle fatigue manifests as an improvement in the amount of time the subject can maintain the required posture.

[0267] For example, cardiovascular endurance may increase, which is the ability of the subject's heart and lungs to supply oxygen to the body. This can also be defined as the ability to perform moderate to high-intensity exercise for an extended period (as a percentage of VO2max). Cardiovascular endurance can be measured using standard methods, including the measurement of VO2max by indirect calorimetry. VO2max is the maximum amount of oxygen an individual can utilize during strenuous or maximal exercise, and is typically measured on a treadmill or cycle ergometer by determining the inspiratory and expiratory volumes and gas concentrations while the person performs maximal intensity graded exercise. VO2max can also be expressed as liters of oxygen consumed per minute (l / min), or, normalized for differences in body size, as milliliters of oxygen consumed per kilogram of body weight per minute (ml / kg / min). Therefore, an increase in cardiovascular endurance can be observed as an increase in VO2max (l / min) or (ml / kg / min) using this assay.

[0268] For example, an increase in cardiovascular health is possible. Cardiovascular health is the body's maximum capacity to take in oxygen. This is also measured as VO2max (L O2 / min). Therefore, an increase in cardiovascular health may be observed as an increase in VO2max (l / min) or (ml / kg / min).

[0269] For example, decreased exercise intolerance can occur. Exercise intolerance is a decrease in the body's ability to perform strenuous physical activity, which may involve being unable to perform physical activity at a normal level or for a normal duration, or a reduced ability to do so. Objective tests for exercise intolerance include moderate activity tests such as stair climbing, the 6-minute walk test, the shuttle walk test, cardiac stress tests, and cardiopulmonary exercise testing (CPET). The 6-minute walk test aims to see how far a person can walk, and for an average person without exercise intolerance, approximately 600 meters is a reasonable result. Therefore, decreased exercise intolerance can be observed as an increase in the distance that can be walked in the 6-minute test.

[0270] For example, an increase in exercise capacity, which is the maximum amount of physical work a patient can sustain, may occur. This can be assessed by maximal exercise testing (e.g., EST, a symptom-limiting test performed using a 12-lead electrocardiogram used to diagnose exercise-induced myocardial ischemia, arrhythmia, or abnormal blood pressure response, or cardiopulmonary exercise testing), submaximal exercise testing, a 6-minute walk test, and an incremental shuttle walk test, with the appropriate test selected according to the subject's physical condition. Therefore, an increase in exercise capacity may be observed as an increase in the score obtained in any of these assessments.

[0271] For example, there may be a decrease in exercise-induced fatigue (EF), which is a decrease in maximum voluntary muscle strength resulting from strenuous, prolonged exercise. Generally, this is measured by observing the fatigue level after high-intensity, prolonged exercise.

[0272] Much of the improvement in muscle function is based on observation by medical professionals and is not quantifiable; however, increases or improvements may be observed by medical professionals based on standard tests for muscle function used in the art. Such quantifiable increases or improvements may be increases or improvements in performance, determined by improved scores or values ​​of at least 1, 2, 3, 5, 10, 15, 20, 25, 30, and 35% at least 1, 2, 3, 4, 5, 6, 12, 18, 24, and 36 months after administration of an FGFR3 signaling inhibitor, NPR-B agonist, or NPR-C agonist, compared to values ​​without or before administration (whether the actual value increases or decreases depends on the nature of the test). In some cases, biochemical assays on muscle biopsies or biochemical assays on muscle metabolites released into body fluids may be used in these methods to yield quantitative results.

[0273] As described above, improvement in muscle function can be defined as an improvement in muscle function compared to or before administration of FGFR3 signaling inhibitors or NPR-B agonists or NPR-C agonists. Therefore, in certain embodiments, subjects treated with FGFR3 signaling inhibitors or NPR-B agonists or NPR-C agonists may still have an overall decline in muscle function (e.g., over time), but in these embodiments, this decline in muscle function may be smaller than the decline that would occur in the absence of treatment. In any such embodiments, improvement in muscle function may manifest as a reduction in the decline of muscle function (e.g., compared to the decline of muscle function in the absence of treatment). This is particularly true in the case of conditions referred herein as diseases or conditions associated with neuromuscular dysfunction, e.g., neuromuscular diseases or neurodegenerative diseases. This may mean that it takes longer for a subject to reach a certain level of muscle function than would be expected based on the subject's diagnosis. In other words, disease progression (e.g., in terms of muscle function) is slower, such that it takes at least 1, 2, 3, or 6 months, or at least 1, 2, or 3 years, to reach a predetermined point in disease progression compared to the absence of treatment.

[0274] Furthermore, improvement in musculoskeletal pain in the subject may also occur. Musculoskeletal pain is defined as acute or chronic pain affecting bones, muscles, ligaments, tendons, and even nerves. This pain can encompass many different pain syndromes, from local pain to neuropathic pain. Musculoskeletal pain is essentially primarily physical. The most common forms of musculoskeletal pain are chronic low back pain and neck pain.

[0275] Musculoskeletal pain can be pain in the musculoskeletal system, including, for example, joints, ligaments, muscles, nerves, or tendons. In some embodiments, musculoskeletal pain may be chronic pain, typically lasting 12 weeks or more. In some embodiments, musculoskeletal pain may be muscle pain, such as chronic skeletal muscle pain. In some embodiments, musculoskeletal pain may be pain associated with abnormal curvature of the spine. In some embodiments, the pain may not be associated with arthritis, such as osteoarthritis. In some embodiments, musculoskeletal pain may be muscle pain. In some embodiments, musculoskeletal pain may be associated with or caused by muscle spasms or cramps. Muscle pain can be diagnosed or monitored, for example, by patient-reported pain (see, e.g., Nielsen and Arendt-Nielsen, Curr Pain Headache Rep. 2003 Dec;7(6):443-51); MRI or CT scans; or electromyography to measure the electrical activity of nerves and muscles.

[0276] Furthermore, improvements in posture or a reduction in abnormal spinal curvature may also occur. Poor or bad posture can be defined as postural dysfunction, where the spine in question is positioned in an unnatural location and the curve is exaggerated. Complications of poor posture include lower back pain, spinal dysfunction, joint degeneration, rounded shoulders, and a protruding abdomen. Improvements related to posture and spinal curvature after administration of FGFR3 signaling inhibitors or NPR-B agonists or NPR-C agonists may result from the aforementioned improvements in muscle function. This is consistent with the observations in Example 1, where treatment with test compound (1) affected survival as early as 15 days after treatment, a timeframe consistent with the effects on historical muscle survival, and an increased incidence of maternal infanticide was described in a mouse model with muscle weakness as the primary phenotypic trait (e.g., Sullivan 2014).

[0277] Kyphosis, lordosis, scoliosis, or spinal stenosis can be improved, and may arise from any of the above spinal malformations. Kyphosis is an exaggerated curvature of the upper part of the spine, causing it to curve forward. Lordosis is a condition in which the spine is greatly curved inward. Scoliosis is an abnormal lateral curvature of the spine. Spinal stenosis is a narrowing of the spinal canal, which may arise from any of the above spinal malformations, for example. In some cases, improvement in kyphosis, lordosis, spinal stenosis, or scoliosis is due to improved muscle function. These spinal abnormalities can occur in chondrodysplasia, and preferably, subjects with kyphosis, lordosis, spinal stenosis, or scoliosis have a disease selected from the group consisting of chondrodysplasia, for example, chondrodysplasia, hypochondroplasia, and fatal osteodysplasia.

[0278] Abnormal curvature of the spine can be monitored, for example, by physical examination or imaging techniques (e.g., X-ray examination, spinal X-ray, CT scan, or MRI scan). Signs of abnormal spinal curvature may include, for example, uneven shoulders, the head not being properly positioned above the pelvis, one or both sides of the hips being elevated or abnormally high, uneven hips, and body tilt. Spinal curvature can be measured, for example, using the Cobb method.

[0279] Improvements in spinal malformations, such as kyphosis (including thoracic and thoracolumbar kyphosis) and lordosis, such as lumbar lordosis, can be measured or monitored by point morphometry of the vertebrae. Point morphometry before, during, or after treatment can be used to detect changes in the shape of the vertebral bodies. For example, spinal malformations in achondroplasia can lead to deformed vertebrae and kyphosis, such as thoracolumbar kyphosis. Kyphosis, such as thoracolumbar kyphosis, can also be caused or further aggravated by muscle weakness / hypotonia. As illustrated herein, in the treatment of children with open apophysitis, the present invention can be used, for example, to prevent or correct vertebral malformations, including vertebral morphology (e.g., reduced apical wedge formation of vertebral L1 and / or L2). In pediatric and adult subjects, improvements in physical function, such as improved muscle function / reduced hypotonia, are also therapeutically beneficial.

[0280] Further embodiments for the treatment of abnormal curvature of the spine. In some embodiments, the present invention relates to the treatment of spinal malformations in subjects having chondrodysplasia, such as chondrodysplasia as disclosed herein, such as chondrodysplasia. Spinal malformations in chondrodysplasia, such as chondrodysplasia, can cause pain and disability. Congenital spinal stenosis is common in chondrodysplasia, and may be associated with neurological symptoms that worsen with age, leading to premature or sudden death, and may require corrective surgery or repeated corrective surgery at some point in the patient's life.

[0281] Spinal malformations may include abnormal curvature of the spine, which can preferably be corrected at least partially by strengthening the back muscles through therapeutic uses disclosed or claimed herein. Spinal malformations may be pedicle malformations or spinal stenosis, which are typical of chondrodysplasia and may be further aggravated by abnormal curvature of the spine. Pedicle malformations may be a reduction in interpedicle distance or a reduction in pedicle width. In chondrodysplasia, narrowing of the interpedicle distance and thickening of the pedicle are common, and the resulting spinal stenosis often requires surgical intervention, such as correcting stenosis of the foramen magnum (FM).

[0282] The present invention provides the use of an FGFR3 signaling inhibitor or an NPR-B agonist for use according to the present invention or for use according to any one of the claims, wherein the use results in increased spinal height, for example, increased thoracic height; increased interpedicle distance or increased pedicle width.

[0283] The present invention provides the use of an NPR-B agonist for use according to the present invention or for use according to any one of the claims, wherein the use results in increased spinal height, for example, increased thoracic height, increased interpedicle distance, or increased pedicle width. The present invention also provides a method for treating spinal pedicle malformations in a subject requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor or an NPR-B agonist to the subject. Preferably, the method may comprise the first step of (i) diagnosing or measuring spinal pedicle malformations in the subject, and then (ii) administering a therapeutically effective amount of an FGFR3 signaling inhibitor or an NPR-B agonist to the subject. Preferably, the measurement step may include one or more X-rays, for example, anterior-posterior (AP) X-rays or lateral X-rays. Lateral X-rays are useful for measuring, for example, pedicle width, and AP X-rays are useful for measuring, for example, interpedicle distance. X-rays of the spine or spinal malformations taken before and after administration can be used to determine effective treatment. Diagnostic or measurement steps may include measuring one or more of the spinal height, thoracic height, interpedicle distance, and pedicle width. Diagnostic measurement steps may include or may include measuring spinal pedicle morphology or spinal stenosis / spine stenosis.

[0284] In certain embodiments, administration results in improvement of sleep apnea, obstructive sleep apnea, or otitis media. Sleep apnea is a condition in which a subject's breathing repeatedly stops and resumes during sleep. This can lead to insufficient oxygen supply to the subject's body. Obstructive sleep apnea (OSA) is a form of sleep apnea that occurs when the throat muscles relax, obstructing airflow to the lungs. Otitis media is an infection of the middle ear, causing inflammation (redness and swelling) and fluid accumulation behind the eardrum, often accompanied by midfacial hypoplasia. Otitis media can cause hearing loss. In some cases, improvement of sleep apnea, obstructive sleep apnea, or otitis media is due to improved muscle function. These conditions can occur in chondrodysplasia, and preferably, subjects with sleep apnea, obstructive sleep apnea, or otitis media have chondrodysplasia, for example, a disease selected from the group consisting of chondrodysplasia, hypochondrodysplasia, and fatal dysplasia. Given the association between sleep-disordered breathing and upper airway (e.g., laryngeal and pharyngeal) muscle weakness, it is thought that improving muscle function may yield benefits in these conditions.

[0285] In some embodiments, the present invention relates to a method for treating obstructive sleep apnea. Sleep apnea, such as obstructive sleep apnea, can be monitored, for example, via nocturnal polysomnography / using a respiratory monitor.

[0286] Otitis media is defined as an infection of the middle ear cavity and is typically diagnosed and monitored by physical examination. Several diagnostic tools are available, including pneumatic otoscopes, tympanometry, and acoustic reflectivity. Otitis media is often accompanied by ear pain, hearing loss, and fever, which can also be monitored. In some embodiments, otitis media is acute otitis media, and the present invention provides an effective treatment that can reduce the frequency of acute otitis media events, reduce the severity of acute otitis media, or both. In some embodiments, the present invention relates to the preventive treatment of otitis media. Therefore, monitoring of otitis media may involve evaluating the frequency or severity of acute otitis media events, or both.

[0287] In certain embodiments, administration results in a reduction of obesity. If the subject suffers from reduced muscle function before treatment, this makes it difficult for the subject to exercise, which is detrimental to weight control and general physical health, and to exercise effectively. By improving the subject's muscle function, a reduction in obesity can also be achieved. This issue has been observed in patients with achondroplasia, and obesity has been noted as a major health problem in achondroplasia, requiring early and complex clinical management (see Saint-Laurent, C., Garde-Etayo, L. & Gouze, E. Obesity in achondroplasia patients: from evidence to medical monitoring Orphanet J Rare Dis 14, 253 (2019). https: / / doi.org / 10.1186 / s13023-019-1247-6). This indicates that children with achondroplasia are limited by their psychomotor development and physical condition, and the early onset of overweight and obesity exacerbates a sedentary lifestyle and / or contributes to their exclusion from sports practiced by children of the same age. In some cases, a reduction in obesity is due to improved muscle function. Obesity may occur in chondrodysplasia, and preferably, subjects with obesity have a disease selected from the group consisting of chondrodysplasia, such as chondrodysplasia, hypochondroplasia, and fatal osteodysplasia.

[0288] Obesity is defined as a body mass index (BMI) greater than 30. Therefore, a reduction in obesity may be a reduction in BMI. Subjects may have a BMI greater than 30 at the start of administration, for example, a BMI greater than 30, 32, 35, 38, or 40 before administration. In certain embodiments, subjects may have a BMI of 25-30 before administration, for example, a BMI greater than 26, 27, 28, or 29.

[0289] Embodiments relating to hand length Hand deformities are characteristic of achondroplasia and include short fingers, tridentary hand deformities, and inability to fully extend fingers.

[0290] The present invention provides an FGFR3 signaling inhibitor or NPR-B agonist for use in promoting hand length or finger length growth in human subjects under 18 years of age or whose epiphyses have not yet closed.

[0291] The present invention provides an FGFR3 signaling inhibitor or NPR-B agonist for use in correcting hand deformities in humans under 18 years of age or those whose epiphyses have not yet closed.

[0292] The present invention provides an FGFR3 signaling inhibitor or NPR-B agonist for use according to the present invention or for use as described in any one of the claims, wherein the use increases hand length growth or finger length growth in human subjects, for example, human subjects under 18 years of age or whose epiphyses have not closed.

[0293] The present invention provides a method for increasing the proportion of hand or finger length in a subject requiring treatment, the method comprising the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor or an NPR-B agonist to the subject.

[0294] Preferably, the method of the present invention may include the steps of (i) evaluating the length of the hand or finger(s) in a subject requiring treatment, (ii) administering a therapeutically effective dose of an FGFR3 signaling inhibitor or NPR-B agonist to the subject, and (iii) optionally measuring the increase in the length of the hand or finger(s) after the administration.

[0295] The present invention provides a method for correcting a hand deformity in a subject requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of an FGFR3 signaling inhibitor or an NPR-B agonist to the subject.

[0296] Preferably, the method of the present invention may include the steps of (i) evaluating hand deformities in a subject requiring treatment, (ii) administering a therapeutically effective amount of an FGFR3 signaling inhibitor or NPR-B agonist to the subject, and (iii) optionally evaluating changes in hand deformities in the subject after the administration.

[0297] Methods that include evaluation steps In certain embodiments, the present invention provides a method for improving muscle function in subjects suffering from a disease or condition that impairs muscle function. The method comprises the steps of evaluating muscle function at least once in subjects suffering from a disease or condition that impairs muscle function, and administering a therapeutically effective dose or regimen of an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist to the subjects.

[0298] This is a method for improving muscle function in a subject suffering from a disease or condition that impairs muscle function, wherein the above method is (i) A step of evaluating muscle function at least once in a subject suffering from a disease or condition that impairs muscle function, and (ii) A step of administering a therapeutically effective dose of an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist to the target. The above methods, including the above, can be described.

[0299] The evaluation step can be performed prior to the administration step, for example, to determine a baseline value or determination of muscle function before administration begins. This may be useful for comparison with subsequent values ​​or determinations of muscle function that may be evaluated after administration. For example, in such cases, the evaluation step can be performed up to one week, one month, or three months before administration begins. The pre-administration evaluation step can be used, for example, as a comparison to determine the effectiveness of the treatment. The administration step can be initiated in response to the evaluation step.

[0300] The administration step generally includes administering an FGFR3 signaling inhibitor, an NPR-B agonist, or an NPR-C agonist multiple times. Muscle function may be assessed at least twice, or more times. In some cases, it may be performed once or at least once before initiating the administration step (e.g., to determine baseline) and once or at least once after initiating the administration step. The assessment step may also be performed at least three times, once or at least once before initiating the administration step (e.g., to determine baseline) and twice or at least twice after initiating the administration step.

[0301] Comparing muscle function determined before initiating an administration step with muscle function determined after initiating an administration step, or comparing sequential determinations of muscle function, or using periodic determinations of muscle function to observe trends in muscle function, for example, in response to treatment, may be beneficial. This can be used to determine treatment outcomes or to inform modifications to the treatment protocol.

[0302] Prior to administration, the assessment of muscle function can also be used, in conjunction with other signs or symptoms of the subject, to diagnose whether the subject is suffering from a disease or condition that impairs muscle function. Therefore, the methods referred to herein may further include a step of diagnosing whether the subject is suffering from impaired muscle function and / or a disease or condition that impairs muscle function. Administration may be initiated in response to the assessment step and / or in response to the diagnosis of the disease or condition in the subject. Administration may also be initiated in response to an assessment of impaired muscle function against a reference value, for example, obtained by an assessment performed on a normal subject or a control subject (e.g., a subject known not to be suffering from a disease or condition that impairs muscle function).

[0303] The evaluation step can be performed additionally or alternatively after the start of administration, for example, during a series of drug administrations. The evaluation step performed after the start of administration can be performed once or multiple times. The evaluation step can be performed at least four, five, six, seven, eight, nine, or ten times, for example, once a week, once a month, once a year, or for example, regularly. The evaluation step can be performed during the treatment period.

[0304] Assessment of muscle function may include any of the following: a) skeletal muscle strength, b) skeletal muscle tone, c) skeletal muscle stamina, d) skeletal muscle mass, e) skeletal muscle fatigue, f) cardiovascular endurance, g) cardiovascular health, h) exercise intolerance, i) exercise capacity, j) exercise-induced fatigue, k) hypotonia, l) skeletal muscle mass and / or muscle / fat ratio (e.g., skeletal muscle / fat ratio), m) musculoskeletal pain, n) spinal posture or curvature, optionally kyphosis, lordosis, spinal stenosis, or scoliosis, o) sleep apnea, obstructive sleep apnea, or otitis media, or p) obesity.

[0305] Such assessments include those described elsewhere in this specification. Examples include measurements of muscle weight, muscle length, muscle density, muscle size, and / or muscle volume. Assessments may include imaging of the subject to observe the subject's performance. Assessments may also be based on physical tests, such as the presence or absence of quantitative measures in muscle fatigue and cardiovascular tests, or by biochemical assays in muscle biopsies, or relating to muscle metabolites released into body fluids.

[0306] The assessment may include imaging studies, such as at least one imaging step (e.g., X-ray examination, spinal X-ray, CT scan, or MRI scan).

[0307] The assessment may include, for example, a step of determining performance metrics for the subject, which may be, for example, a measurement or observation of the subject's ability to perform a specific task, with reference to physical function tests, for example, those described elsewhere in this specification (e.g., those for determining muscle fatigue and endurance levels, e.g., sit-to-stand tests and 6-minute walk tests).

[0308] If more than one evaluation is performed, a composite index may be generated. In certain embodiments, the composite index is generated for at least two, three, four, five, six, and seven (or one to six, two to five, and three to four) of any evaluations performed, for example, at least two, three, four, five, six, and seven (or one to six, two to five, and three to four) of the evaluations a) to p) described above. If a composite index is generated, it can form the basis for any comparisons mentioned elsewhere in this specification.

[0309] Improvement in muscle function may be any improvement in muscle function as defined elsewhere in this specification.

[0310] In some methods, the assessment step is performed at least once before the administration step begins, for example, to determine baseline values ​​or determinations of muscle function, and one, two, or more times after the administration begins, for example, to determine changes in muscle function in response to administration.

[0311] A comparison of muscle function values ​​before and after administration can indicate an increase in muscle function, no change in muscle function, or a decrease in muscle function. An increase in muscle function after and in response to the start of administration can be one indicator of a positive response to treatment, i.e., the success of the treatment.

[0312] In some embodiments, an increase in muscle function, a gradual increase with further administration, an increase in muscle function if muscle function was impaired in the subject before treatment, or a decrease in muscle function observed in past control subjects are indicators of a positive response to treatment.

[0313] Findings indicating no change or a decrease in muscle function may indicate a positive response to treatment, or they may indicate the need for changes in the treatment protocol (e.g., increased dosage and / or frequency), depending on the specific conditions and expected outcomes. For example, in subjects whose muscle function was impaired but stable before drug administration, no change or decrease in muscle function after drug administration may be an indicator of a negative response to treatment. However, if muscle function was impaired and decreased in the subject before drug administration, no change in muscle function after and in response to drug administration may indicate a positive response to treatment. Similarly, a decrease in muscle function after drug administration may indicate a positive response to treatment even if it is less than expected based on the decrease in the subject before administration or in previous untreated control subjects. A decrease in muscle function that exceeds any expectation based on the decrease in the subject before drug administration or in previous untreated control subjects may indicate a negative response to drug administration. Expectations may depend on comparison with control values ​​(may be multiple) determined in the same subject, reference subject, or normal and / or control subject before drug administration.

[0314] The evaluation of changes in muscle function in response to administration can be used as a guide for treatment decisions, such as whether to continue drug administration, change the drug regimen (e.g., change the dosage or frequency), or discontinue drug administration. For example, if the evaluation shows a positive response to administration, the same treatment with the same regimen may be continued. Depending on the magnitude of the response and the side effects experienced by the subject, the dosage and / or frequency may also be adjusted upward or downward. For example, the dosage and / or frequency may be increased to enhance the response, or decreased to reduce any side effects. If the evaluation shows a negative response to treatment (or no positive response) and the subject tolerates the drug without unacceptable side effects, an attempt may be made to elicit a positive therapeutic response by administering a higher dose or frequency of the same drug. If the evaluation continues to show a negative response to treatment (or no positive response) or if the subject cannot tolerate a higher dose or frequency due to side effects, drug administration may be discontinued.

[0315] The evaluation step may follow any of the treatment methods mentioned herein. For example, the present invention provides one of the methods described in items 34 to 114.

[0316] Methods relating to the treatment or prevention of diseases or conditions associated with neuromuscular dysfunction in a subject, such as neurodegenerative diseases, may similarly incorporate an assessment step relating to the determination of muscle function (e.g., skeletal muscle function, as mentioned above). Alternatively or additionally, such methods may incorporate an assessment step relating to mitochondrial dysfunction and the determination of neuromuscular function to establish, for example, whether the treatment results in a slowing, delaying, or reduction of disease progression, such as a reduction in the rate of loss or decline of muscle function, or a reduction in the rate of loss or decline of neuromuscular function.

[0317] Combined use with growth hormone Human growth hormone is approved in Japan for the treatment of chondrodysplasia in children, and combination therapy with CNP is currently under clinical study. Combination therapy with growth hormone in the method and use of the present invention is expected to be advantageous.

[0318] In some embodiments, the growth hormone is somatropin or contains somatropin, or is a somatropin conjugate, such as PEGylated somatropin, or a fatty acid growth hormone conjugate.

[0319] In some embodiments, the growth hormone is a growth hormone conjugate, such as a human growth hormone conjugate. The conjugate portion may include, for example, a PEG portion, a fatty acid portion, a serum albumin-binding portion, an antibody portion, or an antibody fragment portion.

[0320] In some embodiments, the growth hormone is a long-acting growth hormone, such as a growth hormone administered once a week. For example, the long-acting growth hormone may be administered once a week or less frequently.

[0321] Preferably, the growth hormone may be a controlled-release hGH. Long-acting human growth hormone and controlled-release hGH are disclosed in WO2018 / 060314A1, which is incorporated herein by reference in its entirety.

[0322] In some embodiments, the growth hormone is lonapegsomatropin (lonapegsomatropin-tcgd). In some embodiments, the growth hormone conjugate, e.g., human growth hormone conjugate, long-acting human growth hormone, or controlled-release hGH, e.g., lonapegsomatropin, is administered to the subject in a dose ranging from about 0.021 mg / kg / week to about 0.7 mg / kg / week, e.g., 0.21 mg / kg / week or about 0.21 mg / kg / week (mg / kg refers to the mass of growth hormone polypeptide excluding the conjugate portion administered per week).

[0323] In some embodiments, the growth hormone is selected from the group consisting of somapacitan or somapacitan-beko (marketed as SOGROYA® Novo Nordisk), somatorogon (marketed as NGENLA® by Pfizer / OPKO), eftansomatropin alpha (also known as eftansomatopine), efpegsomatropin, albumosomatropin, somabalatan, ibutamoren, and lonapegsomatropin-tcgd.

[0324] Exemplary administration protocols for CNP drugs, such as drugs containing CNP conjugates, such as CNP of formula (IIf') or formula (IIf), or compound (1). For example, the solid unit dosage form is reconstituted before subcutaneous administration to patients requiring subcutaneous administration. Reconstitution of the solid unit dosage form into a reconstituted formulation is carried out by adding a predetermined amount of reconstitution solution to the solid unit dosage form. Therefore, a further aspect of the present invention is a method for reconstituting the solid unit dosage form of the present invention, wherein the above method is as follows: (a) Step of bringing the solid unit dosage form of the present invention into contact with the reconstituted solution. The above method includes the following:

[0325] Reconstitution may be performed in a container in which the solid unit dosage form is provided, for example, a vial; a syringe, for example, a dual-chamber syringe; an ampoule; a cartridge, for example, a dual-chamber cartridge, or the solid unit dosage form may be transferred to a different container and subsequently reconstituted there. In certain embodiments, the container in which the reconstitution of the solid unit dosage form is performed is a vial. In certain embodiments, the container in which the reconstitution of the solid unit dosage form is performed is a syringe. In certain embodiments, the container in which the reconstitution of the solid unit dosage form is performed is a dual-chamber syringe. In certain embodiments, the container in which the reconstitution of the solid unit dosage form is performed is a cartridge. In certain embodiments, the container in which the reconstitution of the solid unit dosage form is performed is a dual-chamber cartridge.

[0326] In certain embodiments, the solid unit dosage form according to the present invention is provided in the first chamber of a dual-chamber syringe, and the reconstituted solution is provided in the second chamber of the dual-chamber syringe.

[0327] The reconstitution solution is a sterile solution such as water or a buffer, and may contain further additives such as preservatives and / or antimicrobial agents.

[0328] In certain embodiments, the reconstituted solution contains one or more preservatives and / or antimicrobial agents and / or antioxidants.

[0329] In certain embodiments, the reconstituted solution contains one or more preservatives.

[0330] The preservative can be selected from the group consisting of m-cresol, benzoic acid, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, potassium sorbate, chlorobutanol, benzyl alcohol, phenylmercury nitrate, thimerosal, sorbic acid, potassium sorbate, chlorocresol, benzalkonium chloride, 2-ethoxyethanol, chlorhexidine, chlorobutanol, phenylethyl alcohol, phenylmercury acetate, and mixtures thereof.

[0331] In certain embodiments, the preservative is m-cresol. In certain embodiments, the preservative is benzyl alcohol. In certain embodiments, the preservative is benzoic acid. In certain embodiments, the preservative is phenol. In certain embodiments, the preservative is methylparaben. In certain embodiments, the preservative is ethylparaben. In certain embodiments, the preservative is propylparaben. In certain embodiments, the preservative is butylparaben. In certain embodiments, the preservative is potassium sorbate. In certain embodiments, the preservative is benzyl alcohol. In certain embodiments, the preservative is phenylmercury nitrate. In certain embodiments, the preservative is thimerosal. In certain embodiments, the preservative is sorbic acid. In certain embodiments, the preservative is potassium sorbate. In certain embodiments, the preservative is chlorocresol. In certain embodiments, the preservative is benzalkonium chloride. In certain embodiments, the preservative is 2-ethoxyethanol. In certain embodiments, the preservative is chlorhexidine. In certain embodiments, the preservative is chlorobutanol. In certain embodiments, the preservative is phenylethyl alcohol. In certain embodiments, the preservative is phenylmercury acetate.

[0332] In certain embodiments, the preservative has a concentration of 1 to 10 mg / ml. In certain embodiments, the preservative has a concentration of 1.5 to 3.5 mg / ml. In certain embodiments, the preservative has a concentration of 2 to 3 mg / ml.

[0333] The antioxidant can be selected from the group consisting of methionine, butylhydroxytoluene, butylhydroxyanisole, tocopherol, propyl gallate, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), poly(ethyleneimine), vitamin E, and mixtures thereof.

[0334] In certain embodiments, the preservative is methionine. In certain embodiments, the preservative is butylhydroxytoluene. In certain embodiments, the preservative is butylhydroxyanisole. In certain embodiments, the preservative is tocopherol. In certain embodiments, the preservative is propyl gallate. In certain embodiments, the preservative is ethylenediaminetetraacetic acid. In certain embodiments, the preservative is poly(ethyleneimine). In certain embodiments, the preservative is vitamin E.

[0335] The term “methionine” as defined herein is intended to encompass both D-methionine and L-methionine, and mixtures thereof. In certain embodiments, the term “methionine” refers to L-methionine. In certain embodiments, the term “methionine” refers to D-methionine. In certain embodiments, the term “methionine” refers to a mixture of D-methionine or L-methionine. In certain embodiments, the term “methionine” refers to L-methionine hydrochloride.

[0336] The term "EDTA" as defined herein is intended to encompass all forms of EDTA known in the art, such as EDTA salts, including, for example, EDTA metal salts, such as EDTA disodium salt, EDTA dipotassium salt, EDTA calcium salt, EDTA dimagnesium salt, or mixtures thereof. In certain embodiments, EDTA refers to EDTA disodium salt. In certain embodiments, the term "EDTA" refers to EDTA dicalcium salt. In certain embodiments, the term "EDTA" refers to EDTA (anhydrous).

[0337] In certain embodiments, the molar ratio of antioxidant to CNP portion is approximately 0.1:1 to approximately 100:1. In certain embodiments, the molar ratio of antioxidant to CNP portion is approximately 0.1:1 to approximately 70:1. In certain embodiments, the molar ratio of antioxidant to CNP portion is approximately 0.1:1 to approximately 15:1. In certain embodiments, the molar ratio of antioxidant to CNP portion is approximately 1:1 to approximately 10:1. In certain embodiments, the molar ratio of antioxidant to CNP portion is approximately 3:1 to approximately 7:1.

[0338] In certain embodiments, the reconstituted solution does not contain an antimicrobial agent. In certain embodiments, the reconstituted solution contains one or more excipients.

[0339] In certain embodiments, the reconstitution solution is sterile water. In certain embodiments, the reconstitution solution is sterile water containing 0.7-1.1% benzyl alcohol. In certain embodiments, the reconstitution solution is sterile water containing 0.9% benzyl alcohol.

[0340] In certain embodiments, the reconstituted solution contains a pH modifier.

[0341] As used herein, the term “pH modifier” refers to a compound used to modify the pH of a reconstituted solution.

[0342] In certain embodiments, the pH modifier may be an acid or an acidic salt thereof. The acid can be selected from the group consisting of acetic acid, citric acid, succinic acid, hydrochloric acid, phosphoric acid, carbonic acid, nitric acid, and mixtures thereof.

[0343] In certain embodiments, the pH modifier may be a base or a basic salt thereof. The base can be selected from the group consisting of Tris (tris(hydroxymethyl)aminomethane), sodium hydroxide, potassium hydroxide, lysine, and mixtures thereof.

[0344] In certain embodiments, the volume of the reconstituted solution is approximately 0.1 ml to approximately 4 ml. In certain embodiments, the volume of the reconstituted solution is approximately 1 ml, for example, approximately 2 ml, for example, approximately 3 ml, or for example, approximately 4 ml.

[0345] In certain embodiments, the volume of the reconstituted solution is approximately 0.79 ml. In certain embodiments, the volume of the reconstituted solution is 0.79 ml. In certain embodiments, the volume of the reconstituted solution is approximately 1 ml. In certain embodiments, the volume of the reconstituted solution is 1 ml. In certain embodiments, the volume of the reconstituted solution is approximately 1.1 ml. In certain embodiments, the volume of the reconstituted solution is 1.1 ml. In certain embodiments, the volume of the reconstituted solution is approximately 1.25 ml. In certain embodiments, the volume of the reconstituted solution is 1.25 ml.

[0346] It is understood that the unit dose volume or injection volume is based on the patient's actual body weight and the concentration of the reconstituted solution. In certain embodiments, the concentration of CNP in the reconstituted solution is 7 mg / ml or less. In certain embodiments, the concentration of CNP in the reconstituted solution is 0.5 mg / ml or more. In certain embodiments, the concentration of CNP in the reconstituted solution is 0.75 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 1 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 2.2 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 3.6 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 4.6 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 5 mg / ml. In certain embodiments, the concentration of CNP in the reconstituted solution is 5.5 mg / ml.

[0347] After reconstitution, the unit dose has a volume of 4 ml or less. In certain embodiments, the volume of the unit dose is approximately 0.01 ml to approximately 1.1 ml. In certain embodiments, the volume of the unit dose is 0.01 ml to 0.75 ml. In certain embodiments, the volume of the unit dose is 0.01 ml to 0.50 ml.

[0348] In certain embodiments, the volume of the unit dose is approximately 0.03 ml. In certain embodiments, the volume of the unit dose is approximately 0.05 ml. In certain embodiments, the volume of the unit dose is approximately 0.1 ml. In certain embodiments, the volume of the unit dose is approximately 0.2 ml. In certain embodiments, the volume of the unit dose is approximately 0.25 ml. In certain embodiments, the volume of the unit dose is approximately 0.3 ml. In certain embodiments, the volume of the unit dose is approximately 0.35 ml. In certain embodiments, the volume of the unit dose is approximately 0.4 ml. In certain embodiments, the volume of the unit dose is approximately 0.5 ml. In certain embodiments, the volume of the unit dose is approximately 0.6 ml. In certain embodiments, the volume of the unit dose is approximately 0.75 ml. In certain embodiments, the volume of the unit dose is approximately 1 ml.

[0349] In certain embodiments, the patient is an infant, and the volume of the unit dose is approximately 10 μl to 100 μl. In certain embodiments, the patient is an infant, and the volume of the unit dose is approximately 10 μl to 50 μl. In certain embodiments, the patient is an infant, and the volume of the unit dose is approximately 10 μl to 30 μl.

[0350] In certain embodiments, the patient is an infant, and the volume of the unit dose is approximately 10 μl. In certain embodiments, the patient is an infant, and the volume of the unit dose is approximately 15 μl. In certain embodiments, the patient is an infant, and the volume of the unit dose is approximately 20 μl.

[0351] In certain embodiments, the patient is an infant, and the unit dose volume is 10 μl. In certain embodiments, the patient is an infant, and the unit dose volume is 15 μl. In certain embodiments, the patient is an infant, and the unit dose volume is 20 μl.

[0352] In certain embodiments, the patient is an infant, the unit dose is 20 μg CNP / kg, and the volume of the unit dose is approximately 10 μl. In certain embodiments, the patient is an infant, the unit dose is 20 μg CNP / kg, and the volume of the unit dose is approximately 15 μl. In certain embodiments, the patient is an infant, the unit dose is 20 μg CNP / kg, and the volume of the unit dose is approximately 20 μl.

[0353] In certain embodiments, the unit dose is 6 μg CNP / kg and the volume of the unit dose is 0.06 ml. In certain embodiments, the unit dose is 20 μg CNP / kg and the volume of the unit dose is 0.3 ml. In certain embodiments, the unit dose is 50 μg CNP / kg and the volume of the unit dose is 0.2 ml. In certain embodiments, the unit dose is 75 μg CNP / kg and the volume of the unit dose is 0.4 ml. In certain embodiments, the unit dose is 100 μg CNP / kg and the volume of the unit dose is 0.5 ml. In certain embodiments, the unit dose is 150 μg CNP / kg and the volume of the unit dose is 0.5 ml.

[0354] In certain embodiments, the pH of the liquid unit dosage form is approximately pH 4 to approximately pH 6. In certain embodiments, the pH of the liquid unit dosage form is approximately pH 4.5 to approximately pH 5.5. In certain embodiments, the pH of the liquid unit dosage form is approximately 5. In certain embodiments, the pH of the liquid unit dosage form is 5.

[0355] In certain embodiments, the unit dosage form of the present invention further comprises a buffer, an isotonicity agent, and a pH modifier.

[0356] In certain embodiments, the buffer has a concentration of 1.3 to 57.6 mM in the unit dosage form. In certain embodiments, the buffer has a concentration of 1.7 to 33 mM in the unit dosage form. In certain embodiments, the buffer has a concentration of 5.1 to 20.3 mM in the unit dosage form. In certain embodiments, the buffer has a concentration of about 10 mM in the unit dosage form.

[0357] Exemplary buffers can be selected from the group consisting of succinic acid, citric acid, lactic acid, acetic acid, glutamic acid, fumaric acid, aspartic acid, glutaric acid, phosphoric acid, histidine, gluconic acid, tartaric acid, malic acid, and mixtures thereof. It will be apparent to those skilled in the art that the corresponding conjugate bases or salts of the above buffers may also be included, for example, succinate, citrate, lactate, acetate, glutamate, fumarate, aspartate, glutarate, phosphate, gluconate, tartrate, malate, and mixtures thereof.

[0358] In certain embodiments, the buffer is succinic acid. In certain embodiments, the buffer is citric acid. In certain embodiments, the buffer is lactic acid. In certain embodiments, the buffer is acetic acid. In certain embodiments, the buffer is glutamic acid. In certain embodiments, the buffer is fumaric acid. In certain embodiments, the buffer is aspartic acid. In certain embodiments, the buffer is glutaric acid. In certain embodiments, the buffer is phosphoric acid. In certain embodiments, the buffer is histidine. In certain embodiments, the buffer is gluconic acid. In certain embodiments, the buffer is tartaric acid. In certain embodiments, the buffer is malic acid.

[0359] The isotonic agent can be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, calcium hydrogen phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethyl starch, dextrose, dextran, Ficoll®, propylene glycol, and mixtures thereof.

[0360] In certain embodiments, the isotonic agent can be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, calcium hydrogen phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethyl starch, dextrose, dextran, propylene glycol, and mixtures thereof.

[0361] In certain embodiments, the isotonic agent is selected from the group consisting of trehalose, sucrose, and glycine. In certain embodiments, the isotonic agent is a non-reducing sugar, such as trehalose or sucrose.

[0362] In certain embodiments, the isotonic agent is trehalose.

[0363] The term "trehalose" as defined herein is intended to encompass all salts and hydrated states of trehalose, such as trehalose (anhydrous) or trehalose dihydrate. In certain embodiments, the term "trehalose" refers to trehalose (anhydrous). In certain embodiments, the term "trehalose" refers to trehalose dihydrate.

[0364] In certain embodiments, the unit dosage form comprises succinic acid and trehalose.

[0365] In a particular embodiment, the unit dosage form is CNP conjugate 0.9~82.1 mg / ml Succinic acid 1.3~57.6 mM Trehalose dihydrate 67-111.6 mg / ml It contains and has a pH of 4.0 to 6.0.

[0366] In a particular embodiment, the unit dosage form is CNP conjugate 19.8~73.6 mg / ml Succinic acid 1.7~50 mM Trehalose dihydrate 63-100 mg / ml It contains and has a pH of 4.0 to 6.0.

[0367] In a particular embodiment, the unit dosage form is CNP conjugate 27.5-50.5 mg / ml Succinic acid 5.1~20.3 mM Trehalose dihydrate 67-95 mg / ml It contains and has a pH of 4.0 to 6.0.

[0368] In certain embodiments, the unit dosage form comprises about 8.2 mg / ml CNP conjugate, about 10 mM succinic acid, about 89 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of about 5.

[0369] In certain embodiments, the unit dosage form comprises 8.2 mg / ml CNP conjugate, 10 mM succinic acid, 89 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of 5.

[0370] In certain embodiments, the unit dosage form comprises about 11 mg / ml CNP conjugate, about 10 mM succinic acid, about 88.5 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of about 5.

[0371] In certain embodiments, the unit dosage form comprises 11 mg / ml CNP conjugate, 10 mM succinic acid, 88.5 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of 5.

[0372] In certain embodiments, the unit dosage form comprises about 24.2 mg / ml CNP conjugate, about 10 mM succinic acid, about 85 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of about 5.

[0373] In certain embodiments, the unit dosage form comprises 24.2 mg / ml CNP conjugate, 10 mM succinic acid, 85 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of 5.

[0374] In certain embodiments, the unit dosage form comprises approximately 39.6 mg / ml CNP conjugate, approximately 10 mM succinic acid, approximately 80 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of approximately 5.

[0375] In certain embodiments, the unit dosage form comprises 39.6 mg / ml CNP conjugate, 10 mM succinic acid, 80 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of 5.

[0376] In certain embodiments, the unit dosage form comprises about 50.5 mg / ml CNP conjugate, about 10 mM succinic acid, about 77 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of about 5.

[0377] In certain embodiments, the unit dosage form comprises 50.5 mg / ml CNP conjugate, 10 mM succinic acid, 77 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of 5.

[0378] In certain embodiments, the unit dosage form comprises approximately 54.9 mg / ml CNP conjugate, approximately 10 mM succinic acid, approximately 75 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of approximately 5.

[0379] In certain embodiments, the unit dosage form comprises 54.9 mg / ml CNP conjugate, 10 mM succinic acid, 75 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of approximately 5.

[0380] In certain embodiments, the unit dosage form comprises approximately 60.4 mg / ml CNP conjugate, approximately 10 mM succinic acid, approximately 73 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of approximately 5.

[0381] In certain embodiments, the unit dosage form comprises 60.4 mg / ml CNP conjugate, 10 mM succinic acid, 73 mg / ml trehalose dihydrate, and optionally Tris and / or hydrochloric acid, and has a pH of 5.

[0382] In a particular embodiment, the unit dosage form is as follows, relative to the total weight of the solid unit dosage form: CNP conjugate 8.2-44.4% (w / w) Succinic acid 0.9-1.2% (w / w) Trehalose dihydrate 53.7-89.1% (w / w) Tris 1.0~1.5% (w / w) Includes.

[0383] In certain embodiments, the unit dosage form contains, based on the total weight of the solid unit dosage form, about 8.2% (w / w) CNP conjugate, about 1.2% (w / w) succinic acid, about 89.1% (w / w) trehalose dihydrate, and about 1.5% (w / w) Tris.

[0384] In certain embodiments, the unit dosage form contains 8.2% (w / w) CNP conjugate, 1.2% (w / w) succinic acid, 89.1% (w / w) trehalose dihydrate, and 1.5% (w / w) Tris, relative to the total weight of the solid unit dosage form.

[0385] In certain embodiments, the unit dosage form contains, based on the total weight of the solid unit dosage form, about 10.7% (w / w) CNP conjugate, about 1.2% (w / w) succinic acid, about 86.8% (w / w) trehalose dihydrate, and about 1.3% (w / w) Tris.

[0386] In certain embodiments, the unit dosage form contains 10.7% (w / w) CNP conjugate, 1.2% (w / w) succinic acid, 86.8% (w / w) trehalose dihydrate, and 1.3% (w / w) Tris, relative to the total weight of the solid unit dosage form.

[0387] In certain embodiments, the unit dosage form contains, based on the total weight of the solid unit dosage form, about 21.6% (w / w) CNP conjugate, about 1.1% (w / w) succinic acid, about 76.1% (w / w) trehalose dihydrate, and about 1.2% (w / w) Tris.

[0388] In certain embodiments, the unit dosage form contains 21.6% (w / w) CNP conjugate, 1.1% (w / w) succinic acid, 76.1% (w / w) trehalose dihydrate, and 1.2% (w / w) Tris, relative to the total weight of the solid unit dosage form.

[0389] In certain embodiments, the unit dosage form contains, based on the total weight of the solid unit dosage form, about 32.4% (w / w) CNP conjugate, about 1.0% (w / w) succinic acid, about 65.4% (w / w) trehalose dihydrate, and about 1.2% (w / w) Tris.

[0390] In certain embodiments, the unit dosage form contains 32.4% (w / w) CNP conjugate, 1.0% (w / w) succinic acid, 65.4% (w / w) trehalose dihydrate, and 1.2% (w / w) Tris, relative to the total weight of the solid unit dosage form.

[0391] In certain embodiments, the unit dosage form contains, based on the total weight of the solid unit dosage form, about 38.9% (w / w) CNP conjugate, about 0.9% (w / w) succinic acid, about 59.2% (w / w) trehalose dihydrate, and about 1% (w / w) Tris.

[0392] In certain embodiments, the unit dosage form contains 38.9% (w / w) CNP conjugate, 0.9% (w / w) succinic acid, 59.2% (w / w) trehalose dihydrate, and 1% (w / w) Tris, relative to the total weight of the solid unit dosage form.

[0393] In certain embodiments, the unit dosage form contains, based on the total weight of the solid unit dosage form, about 41.5% (w / w) CNP conjugate, about 0.9% (w / w) succinic acid, about 56.6% (w / w) trehalose dihydrate, and about 1% (w / w) Tris.

[0394] In certain embodiments, the unit dosage form contains 41.5% (w / w) CNP conjugate, 0.9% (w / w) succinic acid, 56.6% (w / w) trehalose dihydrate, and 1% (w / w) Tris, relative to the total weight of the solid unit dosage form.

[0395] In certain embodiments, the unit dosage form contains, based on the total weight of the solid unit dosage form, about 44.4% (w / w) CNP conjugate, about 0.9% (w / w) succinic acid, about 53.7% (w / w) trehalose dihydrate, and about 1% (w / w) Tris.

[0396] In certain embodiments, the unit dosage form comprises 44.4% (w / w) CNP conjugate, 0.9% (w / w) succinic acid, 53.7% (w / w) trehalose dihydrate, and 1% (w / w) Tris, relative to the total weight of the solid unit dosage form.

[0397] The applicant has surprisingly found that when a unit dosage form of a CNP conjugate, such as a compound of formula (IIf') or formula (IIf), or compound (1) is administered to patients in need, the incidence of hypotension is less than 10%, preferably less than 8%, most preferably less than 5%, and even more preferably less than 3%. In certain embodiments, when a unit dosage form of the present invention is administered to patients in need, the incidence of hypotension is less than 1%. In certain embodiments, there is no incidence of hypotension.

[0398] Furthermore, surprisingly, it was found that anti-CNP antibodies expressed under treatment were not detected during treatment with CNP conjugates (e.g., compounds of formula (IIf') or formula (IIf)). In certain embodiments, anti-CNP binding antibodies were not detected during repeated once-weekly exposure to the conjugates of the present invention for 1 to 9 months. In certain embodiments, anti-CNP binding antibodies were not detected during repeated once-weekly exposure to the conjugates of the present invention for 52 weeks.

[0399] Furthermore, surprisingly, it was found that administration of 100 μg CNP / kg per week (CNP conjugate, e.g., compound (IIf') or compound (IIf) or compound (1)) to pediatric patients aged 2 to 10 years, e.g., 2 to 5 years, or e.g., 5 to 10 years, requiring CNP treatment resulted in a similar response, measured as annual growth rate.

[0400] In a particular embodiment, the CNP portion of the CNP conjugate has the sequence of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 20, 21, 22, 23, 24, or 25. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 20. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 21. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 21. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 22. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 23. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 24. In a particular embodiment, the CNP portion has the sequence of SEQ ID NOs: 25.

[0401] Exemplary CNP conjugates and CNP prodrugs In a particular embodiment, the CNP conjugate is given by formula (Ia) or (Ib): [ka] TIFF2026510974000014.tif15152 (in the formula, -D is the CNP part; -L 1 - is the reversible linker part; -L 2 - represents a single chemical bond or spacer portion; -Z is the polymer part; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16; (y is an integer selected from the group consisting of 1, 2, 3, 4, and 5.) It holds.

[0402] -D in equation (Ia) or (Ib) is -L 1 - is covalently and reversibly conjugated to it.

[0403] In a particular embodiment, x in formula (Ia) is an integer selected from the group consisting of 1, 2, 3, 4, 6, and 8. In a particular embodiment, x in formula (Ia) is an integer selected from the group consisting of 1, 2, 4, and 6. In a particular embodiment, x in formula (Ia) is an integer selected from the group consisting of 1, 4, and 6, and in a particular embodiment, x in formula (Ia) is 1.

[0404] In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 2, 3, 4, and 5. In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 2, 3, and 4. In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 2 and 3. In a particular embodiment, y in formula (Ib) is an integer selected from the group consisting of 1, 2, and 3. In a particular embodiment, y in formula (Ib) is 1. In a particular embodiment, y in formula (Ib) is 2.

[0405] In a particular embodiment, the CNP conjugate has equation (Ia) with x=1.

[0406] In certain embodiments, -D in formula (Ia) or (Ib) has a sequence of SEQ ID NOs: 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30. In certain embodiments, -D in formula (Ia) or (Ib) has a sequence of SEQ ID NOs: 20, 21, 22, 23, 24, or 25.

[0407] In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 20. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 21. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 22. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 23. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 24. In certain embodiments, -D of formula (Ia) or (Ib) has the sequence of sequence number 25.

[0408] In certain embodiments, -D in formula (Ia) or (Ib) has a sequence of sequence numbers 30, 98, 99, or 90.

[0409] Part of equation (Ia) or (Ib) - L 1- is conjugated to a functional group in the side chain of an amino acid residue of -D, or to the N-terminal amine functional group or C-terminal carboxyl functional group of -D, or to a nitrogen atom in the skeletal polypeptide chain of -D. The bond to either the N-terminus or C-terminus may be direct via the corresponding amine functional group or carboxyl functional group, respectively, or the spacer portion may first be conjugated to the amine functional group or carboxyl functional group, followed by the spacer portion -L 1 -It can be indirect, such as conjugating.

[0410] Part of equation (Ia) or (Ib) - L 1 - is a reversible linker from which the drug, namely DH, is released in its free form, i.e., -L 1 - is a traceless linker. Suitable reversible linkers are known in the art, for example, the reversible linker portions disclosed in WO 2005 / 099768 A2, WO 2006 / 136586 A2, WO 2011 / 089216 A1 and WO 2013 / 024053 A1, which are incorporated herein by reference.

[0411] In certain embodiments, -L 1 - is a reversible linker described in WO 2011 / 012722 A1, WO 2011 / 089214 A1, WO 2011 / 089215 A1, WO 2013 / 024052 A1 and WO 2013 / 160340 A1, which are incorporated herein by reference.

[0412] Part-L 1 - can be linked to -D via any type of bond, provided that the bond is reversible. In certain embodiments, -L 1 - is linked to -D via a bond selected from the group consisting of amides, esters, carbamates, acetals, aminals, imines, oximes, hydrazones, disulfides, and acylguanidines. In certain embodiments, -L1 - is linked to -D via a bond selected from the group consisting of amides, esters, carbamates, and acylguanidines. These bonds cannot be reversible in themselves, but -L 1 -It is understood that the adjacent groups contained within can form a reversible bond.

[0413] In certain embodiments, part-L 1 - is bonded to -D via an amide bond.

[0414] Part-L 1 - is disclosed in WO 2009 / 095479 A2. Therefore, in certain embodiments, part -L 1 - is equation (II): [ka] (In the formula, The dashed line indicates the bonding of the CNP moiety, -D, to nitrogen by forming an amide bond, and -X- is -C(R 4 R 4a )-,-N(R 4 )-, -O-, -C(R 4 R 4a )-C(R 5 R 5a )-,-C(R 5 R 5a )-C(R 4 R 4a )-,-C(R 4 R 4a )-N(R 6 )-,-N(R 6 )-C(R 4 R 4a )-,-C(R 4 R 4a )-O-, -OC(R 4 R 4a )-, or -C(R 7 R 7a )- and, X 1 is C, or S(O), -X 2 - is -C(R 8 R 8a)-, or -C(R 8 R 8a )-C(R 9 R 9a )- and, =X 3 is =O, =S, or =N-CN, -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 4 ,-R 4a ,-R 5 ,-R 5a ,-R 6 ,-R 8 ,-R 8a ,-R 9 ,-R 9a -H and C 1-6 Independently selected from the group consisting of alkyls, -R 3 ,-R 3a -H and C 1-6 Independently selected from the group consisting of alkyl, except -R 3 ,-R 3a If one or both of them are not -H, they are sp to the N to which they are bonded. 3 Bonded via hybrid carbon atoms, -R 7 is -N(R 10 R 10a ), or -NR 10 -(C=O)-R 11 And, -R 7a ,-R 10 ,-R 10a ,-R 11 These are, independently of each other, -H or C 1-6 It is alkyl, Depending on the circumstances, Pair-R 1a / -R 4a ,-R 1a / -R 5a ,-R 1a / -R 7a ,-R 4a / -R 5a ,-R 8a / -R 9a One or more of them form a chemical bond, Depending on the circumstances, Pair-R 1 / -R 1a ,-R 2 / -R 2a ,-R 4 / -R 4a ,-R 5 / -R 5a ,-R 8 / -R 8a ,-R 9 / -R 9a One or more of them, together with the atom they are bonded to, C 3-10 Forming a cycloalkyl or 3-10 membered heterocycline, Depending on the circumstances, Pair-R 1 / -R 4 ,-R 1 / -R 5 ,-R 1 / -R 6 ,-R 1 / -R 7a ,-R 4 / -R 5 ,-R 4 / -R 6 ,-R 8 / -R 9 ,-R 2 / -R 3 One or more of these, together with the atoms to which they are bonded, form ring A. Depending on the case, -R 3 / -R 3a These, together with the nitrogen atoms to which they are bonded, form a heterocycle of 3 to 10 members. A is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 (Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclines, and 8-11 membered heterobicyclines.) It has, and here -L 1 - is -L 2 -Z is replaced with -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (II) is -L 2 -Z or not substituted by a substituent, -L 2 - represents a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0415] In a particular embodiment, -L of formula (II) 1 - is one part -L 2 It is replaced by -Z. In certain embodiments, -L of formula (II) 1 - has not been further replaced.

[0416] -R in equation (II) 3 / -R 3a However, when these atoms combine with the nitrogen atom to which they are bonded to form a 3- to 10-membered heterocycle, the atom directly bonded to the nitrogen is sp 3 It is understood that only 3- to 10-membered heterocycles, such as hybridized carbon atoms, can be formed. In other words, -R 3 / -R 3a A 3- to 10-membered heterocycle, formed by the nitrogen atoms to which they are bonded, has the following structure: [ka] (In the formula, The dashed line is -L 1 - indicates the connection to the remainder, The ring contains 3 to 10 atoms, including at least one nitrogen atom. R # and R ## is, sp 3 (Represents hybrid carbon atoms) It holds.

[0417] It is also understood that complex rings with 3 to 10 members may be further permuted.

[0418] -R in equation (II) 3 / -R 3a A suitable exemplary embodiment of a 3- to 10-membered heterocycle formed by these and the nitrogen atoms to which they are bonded is as follows: [ka] (In the formula, The dashed line indicates the bond to the rest of the molecule. -R is -H and C 1-6 (Selected from the group consisting of alkyl groups).

[0419] -L in equation (II) 1 - may be further substituted depending on the case. In general, any substituent may be used as long as it does not affect the principle of cleavage, i.e., the hydrogen with the asterisk in formula (II) is not substituted, and part of formula (II) [ka] The nitrogen remains as part of the primary, secondary, or tertiary amine, i.e., -R 3 and -R 3a These are either -H independently of each other, or sp 3 It is bonded to -N< by hybridized carbon atoms.

[0420] In certain embodiments, -R of formula (II) 1 or -R 1a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 2 or -R 2a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 3 or -R 3a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 4 is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 5 or -R 5a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 6 is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 7 or -R 7a is, -L 2 It is replaced by -Z. In certain embodiments, -R in formula (II) 8 or -R 8a is, -L2 It is replaced by -Z. In certain embodiments, -R in formula (II) 9 or -R 9a is, -L 2 It is replaced with -Z.

[0421] In certain embodiments, -R of formula (II) 4 is, -L 2 It is replaced with -Z.

[0422] In a particular embodiment, -X- in formula (II) is -C(R 4 R 4a )- or -N(R 4 )-. In a particular embodiment, -X- in formula (II) is -C(R 4 R 4a )-is.

[0423] In a particular embodiment, X of formula (II) 1 It is C.

[0424] In a particular embodiment, equation (II) = X 3 The answer is = O.

[0425] In a particular embodiment, -X of formula (II) 2 - is -C(R 8 R 8a )-is.

[0426] In certain embodiments, -R of formula (II) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (II) 8 and -R 8a Both are -H.

[0427] In certain embodiments, -R of formula (II) 1 and -R 1aThe is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 1 and -R 1a At least one of them is -H. In certain embodiments, -R of formula (II) 1 and -R 1a Both are -H.

[0428] In certain embodiments, -R of formula (II) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (II) 2 and -R 2a Both are H.

[0429] In certain embodiments, -R of formula (II) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (II) 3 and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (II) 3 and -R 3a In all cases, these are H. In a particular embodiment, -R of formula (II) 3 and -R 3a These are all methyl. In certain embodiments, -R of formula (II) 3 is -H, and -R in equation (II) 3a It is methyl.

[0430] In certain embodiments, -R of formula (II) 4 and -R 4a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (II) 4 and -R 4a At least one of them is -H. In certain embodiments, -R of formula (II)4 and -R 4a Both are -H.

[0431] In certain embodiments, part-L 1 - is equation (IIa): [ka] (In the formula, The dashed line indicates the bonding of the CNP moiety, -D, to nitrogen by forming an amide bond, and -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 3 ,-R 3a ,-R 4 ,-R 4a and -X 2 - is used as defined in equation (II). It has, Here, -L 1 - is -L 2 -Z is replaced with -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIa) is -L 2 -Z is not substituted by a substituent.

[0432] In a particular embodiment, -L of formula (IIa) 1 - is one part -L 2 -Z is substituted. In certain embodiments, part -L of formula (IIa) 1 - has not been further replaced.

[0433] In certain embodiments, -R of formula (IIa) 1 and -R 1a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) 1 and -R 1a At least one of them is -H. In certain embodiments, -R of formula (IIa) 1 and -R 1a Both are -H.

[0434] In certain embodiments, -R of formula (IIa) 4 and -R 4a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) 4 and -R 4a At least one of them is -H. In certain embodiments, -R of formula (IIa) 4 and -R 4a Both are -H.

[0435] In a particular embodiment, -X of formula (IIa) 2 - is -C(R 8 R 8a )-is.

[0436] In certain embodiments, -R of formula (IIa) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIa) 8 and -R 8a Both are -H.

[0437] In certain embodiments, -R of formula (IIa) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIa) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIa) 2 and -R 2a Both are H.

[0438] In certain embodiments, -R of formula (IIa) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIa) 3and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (IIa) 3 and -R 3a In all cases, -H is the case of formula (IIa). 3 and -R 3a These are all methyl. In certain embodiments, -R of formula (IIa) 3 is -H, and -R in equation (IIa) 3a It is methyl.

[0439] In certain embodiments, part-L 1 - is equation (IIb): [ka] (In the formula, The dashed line indicates the bonding of the CNP moiety, -D, to nitrogen by forming an amide bond, and -R 2 ,-R 2a ,-R 3 ,-R 3a and -X 2 - is used as defined in equation (II). It has, Here, -L 1 - is -L 2 -Z is replaced with -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIb) is -L 2 -Z is not substituted by a substituent.

[0440] In certain embodiments, -L of formula (IIb) 1 - is one part -L 2 -Z is substituted. In certain embodiments, part -L of formula (IIb) 1 - has not been further replaced.

[0441] In a particular embodiment, -X of formula (IIb) 2 - is -C(R 8 R 8a )-is.

[0442] In certain embodiments, -R of formula (IIb) 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb) 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIb) 8 and -R 8a Both are -H.

[0443] In certain embodiments, -R of formula (IIb) 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb) 2 and -R 2a At least one of them is -H. In certain embodiments, -R of formula (IIb) 2 and -R 2a Both are H.

[0444] In certain embodiments, -R of formula (IIb) 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIb) 3 and -R 3a At least one of them is methyl. In certain embodiments, -R of formula (IIb) 3 and -R 3a In all cases, -H is the case of equation (IIb). 3 and -R 3a All of these are methyl. In certain embodiments, -R of formula (IIb) 3 is -H, and -R in equation (IIb) 3a It is methyl.

[0445] In certain embodiments, part-L 1 - is equation (IIb'): [ka] (In the formula, The dashed line indicates the bonding of the CNP moiety, -D, to nitrogen by forming an amide bond, and the dashed line with an asterisk indicates -L 2 - indicates binding to -R 2 ,-R 2a ,-R 3 ,-R 3a , and -X 2 - is used as defined in formula (II), Here, -L 1 - may be further substituted in some cases, except that the hydrogen atom with an asterisk in formula (IIb') is not substituted by a substituent.

[0446] In a particular embodiment, part L of formula (IIb') 1 - has not been further replaced.

[0447] In a particular embodiment, -X in formula (IIb') 2 - is -C(R 8 R 8a )-is.

[0448] In certain embodiments, -R of formula (IIb') 8 and -R 8a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb') 8 and -R 8a At least one of them is -H. In certain embodiments, -R of formula (IIb') 8 and -R 8a Both are -H.

[0449] In certain embodiments, -R of formula (IIb') 2 and -R 2a The is independently selected from the group consisting of -H, methyl, and ethyl. In certain embodiments, the -R of formula (IIb') 2 and -R 2aAt least one of them is -H. In certain embodiments, -R of formula (IIb') 2 and -R 2a Both are H.

[0450] In certain embodiments, -R of formula (IIb') 3 and -R 3a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (IIb') 3 and -R 3a At least one of them is methyl. In certain embodiments, the -R of formula (IIb') 3 and -R 3a In all cases, -R in formula (IIb') 3 and -R 3a All of these are methyl. In certain embodiments, -R of formula (IIb') 3 is -H, and -R in equation (IIb') 3a It is methyl.

[0451] In certain embodiments, part-L 1 - is equation (IIc): [ka] (In the formula, the dashed line indicates the bonding of the CNP portion, -D, to nitrogen by forming an amide bond.) It has, Here, -L 1 - is -L 2 -Z is replaced with -L 1 - is sometimes further substituted, except that the hydrogen with an asterisk in formula (IIc) is -L 2 -Z is not substituted by a substituent.

[0452] In certain embodiments, the -L of formula (IIc) 1 - is one part -L 2 -Z is substituted. In certain embodiments, part -L of formula (IIc) 1 - has not been further replaced.

[0453] In certain embodiments, part-L 1 - is in equations (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv), and (IIc-v): [ka] TIFF2026510974000024.tif35156 (in the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) Selected from the group consisting of, -L 1 - may be further substituted in some cases, except that the hydrogen atoms with an asterisk in formulas (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv) and (IIc-v) are not substituted by substituents.

[0454] In a particular embodiment, part L of formulas (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv) and (IIc-v) 1 - has not been further replaced.

[0455] In certain embodiments, part-L 1 - is equation (IIc-ii): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. The dashed line with an asterisk indicates -L 2 (Indicates bonding to -Z) It holds.

[0456] In a particular embodiment, the -L of formula (IIc-ii) 1 - is one part -L 2It is replaced with -Z.

[0457] -L of formula (II), (IIa), (IIb), (IIb'), (IIc), (IIc-a), (IIc-b), (IIc-i), (IIc-ii), (IIc-iii), (IIc-iv), (IIc-v) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0458] Another part - L 1 - is disclosed in WO2016 / 020373A1. Therefore, in certain embodiments, part -L 1 - is equation (III): [ka] (In the formula, The dashed lines indicate bonding by forming amide or ester bonds to the primary or secondary amine or hydroxyl group of the CNP portion -D, respectively. -R 1 ,-R 1a ,-R 2 ,-R 2a ,-R 3 and -R 3a These are -H, -C(R 8 R 8a R 8b ), -C(=O)R 8 -C≡N, -C(=NR) 8 )R 8a ,-CR 8 (=CR 8a R 8b ), -C≡CR 8 Selected from the group consisting of and -T, -R 4 ,-R 5 and -R 5a These are -H, -C(R 9 R 9a R 9b Selected from the group consisting of ) and -T, a1 and a2 are independently 0 or 1. Each-R 6 ,-R6a ,-R 7 ,-R 7a ,-R 8 ,-R 8a ,-R 8b ,-R 9 ,-R 9a ,-R 9b These are -H, halogen, -CN, and -COOR, which are independent of each other. 10 , -OR 10 , -C(O)R 10 ,-C(O)N(R 10 R 10a ), -S(O)2N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(O)2R 10 ,-S(O)R 10 , -N(R 10 )S(O)2N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -NO2, -OC(O)R 10 , -N(R 10 )C(O)R 10a , -N(R 10 )S(O)2R 10a , -N(R 10 )S(O)R 10a , -N(R 10 )C(O)OR 10a , -N(R 10 )C(O)N(R 10a R 10b ), -OC(O)N(R 10 R 10a ), -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Selected from the group consisting of alkynyls, where -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is one or more identical or different -R 11 In some cases, it is replaced by C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 12 )-,-S(O)2N(R 12 )-,-S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-,-N(R 12 )C(O)N(R 12a )-, and -OC(O)N(R 12 )- may have one or more groups selected from the group, Each-R 10 ,-R 10a ,-R 10b These are independently -H, -T, and C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Selected from the group consisting of alkynyl, where -T, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is one or more identical or different -R 11 In some cases, it is replaced by C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 12 )-,-S(O)2N(R 12 )-,-S(O)N(R 12 )-, -S(O)2-, -S(O)-, -N(R 12 )S(O)2N(R 12a )-, -S-, -N(R 12 )-, -OC(OR 12 )(R 12a )-,-N(R 12 )C(O)N(R 12a )-, and -OC(O)N(R 12 )- may have one or more groups selected from the group, Each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic, where each T is independently one or more of the same or different -R 11 and is optionally substituted with, each -R 11 is independently selected from halogen, -CN, oxo (=O), -COOR 13 , -OR 13 , -C(O)R 13 , -C(O)N(R 13 R 13a ), -S(O)2N(R 13 R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens. Depending on the circumstances, Pair-R 1 / -R 1a ,-R 2 / -R 2a ,-R 3 / -R 3a ,-R 6 / -R 6a ,-R 7 / -R 7a One or more of them, together with the atom they are bonded to, C 3-10 Forming a cycloalkyl or 3-10 membered heterocycline, Depending on the circumstances, Pair-R 1 / -R 2 ,-R 1 / -R 3 ,-R 1 / -R 4 ,-R 1 / -R 5 ,-R 1 / -R 6 ,-R 1 / -R 7 ,-R 2 / -R 3 ,-R 2 / -R 4 ,-R 2 / -R 5 ,-R 2 / -R 6 ,-R 2 / -R 7 ,-R 3 / -R 4 ,-R 3 / -R 5 ,-R 3 / -R 6 ,-R 3 / -R 7 ,-R 4 / -R 5 ,-R 4 / -R 6 ,-R 4 / -R 7 ,-R 5 / -R 6 ,-R 5 / -R 7 ,-R 6 / -R7 One or more of them, together with the atoms to which they are attached, form ring A, A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclic ()) having, where -L 1 - is replaced by -L 2 -Z, -L 1 - is optionally further substituted, -L 2 - is a single chemical bond or a spacer, -Z is a water-soluble polymer moiety.

[0459] The optional further substituent of -L in formula (III) is as described above in certain embodiments. In certain embodiments, -L in formula (III) 1 - is substituted with one moiety -L 1 -Z. In certain embodiments, -L in formula (III) 2 - is not further substituted. 1 - is not further substituted.

[0460] -L 1 Further embodiments for -L are disclosed in European Patent No. 1536334 B1, WO2009 / 009712 A1, WO2008 / 034122 A1, WO2009 / 143412 A2, WO2011 / 082368 A2, and U.S. Patent No. 8,618,124 B2, which are hereby incorporated by reference in their entirety.

[0461] -L 1 Further embodiments for -L are disclosed in U.S. Patent No. 8,946,405 B2 and U.S. Patent No. 8,754,190 B2, which are hereby incorporated by reference in their entirety. Thus, the moiety -L 1 - is of formula (IV):

Chemical formula

[0462] -L in equation (IV) 1 Further optional substituents of - are, in certain embodiments, as described above. In certain embodiments, -L of formula (IV) 1 - is one part -L 2 It is replaced by -Z. In certain embodiments, -L of formula (IV) 1 - has not been further replaced.

[0463] The term used exclusively in relation to formula (IV) has the following meanings:

[0464] As used herein, the term "alkyl" includes linear, branched, or cyclic saturated hydrocarbon groups having 1 to 8 carbon atoms, or in certain embodiments, 1 to 6 or 1 to 4 carbon atoms.

[0465] The term "alkoxy" includes alkyl groups bonded to oxygen, such as methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar groups.

[0466] The term "alkenyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon double bond.

[0467] The term "alkynyl" includes non-aromatic unsaturated hydrocarbons that have a carbon-carbon triple bond.

[0468] The term "aryl" includes aromatic hydrocarbon groups with 6 to 18 carbon atoms, and in certain embodiments, 6 to 10 carbon atoms, such as phenyl, naphthyl, and anthracenyl groups. The term "heteroaryl" includes aromatic rings with 3 to 15 carbon atoms containing at least one N, O, or S atom, and in certain embodiments, aromatic rings with 3 to 7 carbon atoms containing at least one N, O, or S atom, such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl groups, and similar groups.

[0469] In certain embodiments, an alkenyl, alkynyl, aryl, or heteroaryl moiety may be bonded to the remainder of the molecule via an alkylene bond. In such circumstances, the substituent is referred to as an alkenylalkyl, alkynylalkyl, arylalkyl, or heteroarylalkyl, indicating that the alkylene moiety is located between the alkenyl, alkynyl, aryl, or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl, or heteroaryl is bonded.

[0470] The term "halogen" includes bromo, fluoro, chloro, and iodine.

[0471] The term "heterocyclic ring" refers to a 4-8 member aromatic or non-aromatic ring containing 3-7 carbon atoms and at least 1 N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term "heteroaryl" above.

[0472] If the ring system is optionally substituted, preferred substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or additional rings, each of which may be further substituted as an optional substituent on any group including the above, including halo, nitro, cyano, -OR, -SR, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO2R, -SONR2, -SO2NR2, where each R is independently alkyl, alkenyl, alkynyl, aryl, or heteroaryl, or two R groups together with the atom to which they are bonded form a ring.

[0473] -L 1 Further embodiments of - are disclosed in WO2013 / 036857A1, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, part -L 1 - is equation (V): [ka] (In the formula, The dashed line indicates the bond to the CNP portion, -D, where the bond is mediated by the amine functional group of -D. -R 1 These include optionally substituted C1-C6 linear, branched, or cyclic alkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, alkoxy groups, and -NR groups. 5 Selected from a group consisting of 2, -R 2 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 3 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. -R 4 This is selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. Each-R 5 These are independently selected from the group consisting of -H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or together, two -R 5 (This can be a cycloalkyl or cycloheteroalkyl group.) It has, Here, -L 1 - is -L 2 -Z is replaced with -L 1 - is sometimes further replaced by -L 2 - represents a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0474] -L in equation (V) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0475] In certain embodiments, -L of formula (V) 1 - is one part -L 2 It is replaced with -Z.

[0476] In certain embodiments, -L of formula (V) 1 - has not been further replaced.

[0477] The term used exclusively in relation to the expression (V) has the following meanings:

[0478] "Alkyl," "alkenyl," and "alkynyl" refer to linear, branched, or cyclic hydrocarbon groups of 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms, where alkyl is a saturated hydrocarbon, alkenyl contains one or more carbon-carbon double bonds, and alkynyl contains one or more carbon-carbon triple bonds. Unless otherwise specified, these contain 1 to 6 carbon atoms.

[0479] "Aryl" refers to an aromatic hydrocarbon group comprising 6 to 18 carbon atoms, or in specific embodiments, 6 to 10 carbon atoms, such as phenyl, naphthyl, and anthracene. "Heteroaryl" refers to an aromatic ring comprising 3 to 15 carbon atoms, or in specific embodiments, an aromatic ring comprising 3 to 7 carbon atoms, comprising at least one N, O, or S atom, such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indol, indenyl, and similar groups.

[0480] The term "substituted" refers to an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group that contains one or more substituents in place of one or more hydrogen atoms. Substituents commonly include halogens (e.g., F, Cl, Br, and I), lower alkyls (e.g., linear, branched, and cyclic), lower haloalkyls (e.g., fluoroalkyls, chloroalkyls, bromoalkyls, and iodoalkyls), OH, lower alkoxys (e.g., linear, branched, and cyclic), SH, lower alkylthios (e.g., linear, branched, and cyclic), amino, alkylamino, dialkylamino, silyl (e.g., alkylsilyls, alkoxysilyls, and arylsilyls), nitro, cyano, carbonyl, carboxylic acids, carboxylic acid esters, carboxylic acid amides, aminocarbonyls, aminoacyls, carbamates, ureas, and thiocarbamates. The following can be selected: thiourea, ketones, sulfones, sulfonamides, aryls (e.g., phenyl, naphthyl, and anthracenyl), heteroaryls (e.g., 5-membered heteroaryls such as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole; 6-membered heteroaryls such as pyridine, pyrimidine, pyrazine, and condensed heteroaryls such as benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzoisoxazole, and benzoisothiazole).

[0481] -L 1 Another embodiment of -L is disclosed in WO 2022 / 115563 A1, which is incorporated herein by reference in its entirety. Thus, in a particular embodiment, -L 1 - is equation (Va): [ka] (In the formula, The dashed line with an asterisk indicates -L 2 (Dashed lines without a mark indicate connections to -Z, and unmarked dashed lines indicate connections to -D.) It holds.

[0482] In certain embodiments, -L 1 - represents equation (Va), and the dashed line with an asterisk represents -L 2 The dashed line indicates binding to -Z, and the unmarked dashed line indicates binding to -D, where -D is the following amino acid sequence: Sequence ID 97 (CNP-38 N6Q, N14Q): LQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC This is the CNP portion, Here, the cysteine ​​at positions 22 and 38 are linked via a disulfide bridge;-L 1 Binding to the peptide occurs either at the N-terminus or ring of the peptide.

[0483] -L 1 Another embodiment of - is disclosed in U.S. Patent No. 7,585,837 B2, which is incorporated herein by reference in its entirety. Thus, in a particular embodiment, part -L 1 - is equation (VI): [ka] (In the formula, The dashed line indicates the bond to the CNP portion, -D, where the bond is mediated by the amine functional group of -D. R 1 and R 2 These are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkalyl, aralkyl, halogen, nitro, -SO3H, -SO2HH 5 Selected from the group consisting of amino, ammonium, carboxyl, PO3H2 and OPO3H2, R 3 , R 4 and R 5 (is independently selected from the group consisting of hydrogen, alkyl, and aryl), Here, -L 1 - is -L 2-Z is replaced with -L 1 - is sometimes further replaced by -L 2 - represents a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0484] Suitable substituents for formula (VI) are alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 Alkenyl), Alkinyl (for example, C 2-6 The moiety is an alkynyl, aryl (e.g., phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (e.g., an aromatic 4-7 membered heterocycle), or halogen moiety.

[0485] In certain embodiments, -L of formula (VI) 1 - is one part -L 2 It is replaced by -Z. -L in equation (VI) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0486] In certain embodiments, -L of formula (VI) 1 - has not been further replaced.

[0487] The term used exclusively in relation to formula (VI) has the following meanings:

[0488] The terms “alkyl,” “alkoxy,” “alkoxyalkyl,” “aryl,” “alkalic,” and “aralkyl” refer to alkyl groups with 1 to 8 carbon atoms, and in certain embodiments, 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and butyl, and aryl groups with 6 to 10 carbon atoms, such as phenyl and naphthyl. The term “halogen” includes bromo, fluoro, chloro, and iodine.

[0489] -L 1Further embodiments of - are disclosed in WO2002 / 089789A1, which is incorporated herein by reference in its entirety. Therefore, part -L 1 - is equation (VII): [ka] (In the formula, The dashed line indicates the bond to the CNP portion, -D, where the bond is mediated by the amine functional group of -D. L1 is a bifunctional bonding group, Y1 and Y2 are independently O, S, or NR 7 And, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C 1-6 Alkyl, C 3-12 Branched alkyl, C 3-8 Cycloalkyl, C 1-6 Substituting alkyl, C 3-8 Substituted cycloalkyl, aryl, substituted aryl, aralkyl, C 1-6 Heteroalkyl, substituted C 1-6 Heteroalkyl, C 1-6 Alkoxy, phenoxy and C 1-6 Selected from the group consisting of heteroalkoxys, When Ar is included in formula (VII), it is the part that forms a polysubstituted aromatic hydrocarbon or a polysubstituted heterocyclic group. X is a chemical bond, or a portion that is actively transported to the target cell, a hydrophobic portion, or a combination thereof. (y is either 0 or 1) It has, Here, -L 1 - is -L 2 -Z is replaced with -L 1 - is sometimes further replaced by -L 2 - represents a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0490] In certain embodiments, -L of formula (VII) 1 - is one part -L 2 It is substituted with -Z. -L in equation (VII) 1 Further optional substituents of - are, in certain embodiments, as described above.

[0491] In certain embodiments, -L of formula (VII) 1 - has not been further replaced.

[0492] The term used exclusively in relation to formula (VII) has the following meanings: The term "alkyl" refers to, for example, linear, branched, substituted C. 1-12 Alkyl, for example, alkoxy, C 3-8 It is understood that this includes cycloalkyl or substituted cycloalkyl compounds.

[0493] The term "substituted" shall be understood to include adding one or more different atoms to one or more atoms contained in a functional group or compound, or substituting one or more different atoms with one or more different atoms.

[0494] Examples of substituted alkyl groups include carboxyalkyl, aminoalkyl, dialkylamino, hydroxyalkyl, and mercaptoalkyl groups; examples of substituted cycloalkyl groups include 4-chlorocyclohexyl; examples of aryl groups include naphthyl; examples of substituted aryl groups include 3-bromophenyl; examples of aralkyl groups include toluyl; examples of heteroalkyl groups include ethylthiophene; examples of substituted heteroalkyl groups include 3-methoxythiophene; examples of alkoxy groups include methoxy; and examples of phenoxy groups include 3-nitrophenoxy. Halo- is understood to include fluoro, chloro, iodine, and bromo.

[0495] In certain embodiments, -L 1 - is a substructure of equation (VIII) [ka] (In the formula, The dashed line with an asterisk indicates the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Here, -L 1 - is -L 2 -Z is replaced with -L 1 - is sometimes further replaced by -L 2 - represents a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0496] In certain embodiments, the -L of formula (VIII) 1 - is one part -L 2 It is substituted with -Z. -L in equation (VIII) 1 Further optional substituents are as described above.

[0497] In certain embodiments, the -L of formula (VIII) 1 - has not been further replaced.

[0498] In certain embodiments, -L 1 - is a substructure of equation (IX) [ka] (In the formula, The dashed lines with asterisks indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of a carbamate bond. Dashed lines without a mark are -L 1 (Indicates connection to the remainder) Includes, Here, -L 1 - is -L 2-Z is replaced with -L 1 - is sometimes further replaced by -L 2 - represents a single chemical bond or spacer, -Z is the water-soluble polymer portion.

[0499] -L in equation (IX) 1 Further optional substituents of - are as described above. In certain embodiments, -L of formula (IX) 1 - is one part -L 2 It is replaced by -Z. In certain embodiments, -L of formula (IX) 1 - has not been further replaced.

[0500] Part -D is -L via any functional group of DH 1 - is bonded to the amine functional group of DH, via the -L 1 - is bonded. This may be an N-terminal amine functional group, or an amine functional group provided by a lysine side chain, i.e., by lysine at positions 9, 11, 15, 16, 20 and 26, if the CNP has the sequence of SEQ ID NO: 24.

[0501] -L to the ring of the CNP portion 1 The binding of - significantly reduces the affinity of the CNP conjugate to NPR-B compared to binding to the N-terminus or acyclic portion of the CNP, and this reduced affinity to NPR-B subsequently reduces the risk of cardiovascular side effects such as hypotension.

[0502] Therefore, in certain embodiments, -L 1 - is conjugated to the side chain of the amino acid residue of the ring portion of -D, or to the backbone of the ring portion of -D. In certain embodiments, -L 1 - is covalently and reversibly conjugated to the side chain of the amino acid residue of the ring portion of -D. If -D is the CNP portion having the sequence of SEQ ID NO: 24, then -L 1- is conjugated in certain embodiments to an amine functional group provided by lysine at the 26th position of the corresponding drug DH.

[0503] Part-L 2 - represents a chemical bond or spacer portion. In certain embodiments, -L 2 - is a chemical bond. In certain embodiments, -L 2 - indicates the spacer portion.

[0504] Part-L 2 - replaces any existing -H with -L unless explicitly excluded. 1 - Can be bound to

[0505] -L 2 -If it is not a monochemical bond, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; where -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is the same or different of one or more -R y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y3 )-,-S(O)2N(Ry3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may have one or more groups selected from the group consisting of these groups interspersed; -R y1 and -R y1a These are -H, -T, and C, which are independent of each other. 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; where -T, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may have one or more groups selected from the group consisting of these groups interspersed; Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls; where each T is independently one or more identical or different -R y2 It is sometimes replaced by; Each-R y2 These are, independently, halogen, -CN, oxo (=O), and -COOR. y5 , -OR y5 , -C(O)R y5 ,-C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a ), -S(O)N(R y5 R y5a ), -S(O)2R y5 ,-S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 Selected from the group consisting of alkyl groups; where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens; each -R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b These are independently -H and C 1-6Selected from the group consisting of alkyl groups; C 1-6 The alkyl group may be substituted with one or more identical or different halogens.

[0506] -L 2 -If it is not a monochemical bond, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a )-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Selected from the group consisting of alkynnyls; where -T-, C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkinyl is one or more identical or different -R y2 In some cases, it is replaced by C 1-20 Alkyl, C 2-20 Alkenyl and C 2-20 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may have one or more groups selected from the group consisting of these groups interspersed; -R y1 and -R y1a These are -H, -T, and C, which are independent of each other. 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyls; where -T, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyl is one or more identical or different -R y2 In some cases, it is replaced by C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y4 )-,-S(O)2N(R y4 )-,-S(O)N(R y4 )-, -S(O)2-, -S(O)-, -N(R y4 )S(O)2N(R y4a )-, -S-, -N(R y4 )-, -OC(OR y4 )(R y4a )-,-N(R y4 )C(O)N(R y4a )-, and -OC(O)N(R y4 )- may have one or more groups selected from the group consisting of these groups interspersed; Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls; where each T is independently one or more identical or different -R y2 It is sometimes replaced by; -R y2 These are halogen, -CN, oxo (=O), and -COOR. y5 , -OR y5 , -C(O)R y5 ,-C(O)N(R y5 R y5a ), -S(O)2N(R y5 R y5a), -S(O)N(R y5 R y5a ), -S(O)2R y5 ,-S(O)R y5 , -N(R y5 )S(O)2N(R y5a R y5b ), -SR y5 , -N(R y5 R y5a ), -NO2, -OC(O)R y5 , -N(R y5 )C(O)R y5a , -N(R y5 )S(O)2R y5a , -N(R y5 )S(O)R y5a , -N(R y5 )C(O)OR y5a , -N(R y5 )C(O)N(R y5a R y5b ), -OC(O)N(R y5 R y5a ), and C 1-6 Selected from the group consisting of alkyl groups; where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens; Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b These are, independently of each other, -H and C 1-6 Selected from the group consisting of alkyl groups; where C 1-6 The alkyl group may be substituted with one or more identical or different halogens.

[0507] -L 2 -If it is not a monochemical bond, -L 2 - stands for -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y1 )-,-S(O)2N(R y1 )-,-S(O)N(R y1 )-, -S(O)2-, -S(O)-, -N(R y1 )S(O)2N(R y1a)-, -S-, -N(R y1 )-, -OC(OR y1 )(R y1a )-,-N(R y1 )C(O)N(R y1a )-,-OC(O)N(R y1 )-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; where -T-, C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R y2 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) y3 )-,-S(O)2N(R y3 )-,-S(O)N(R y3 )-, -S(O)2-, -S(O)-, -N(R y3 )S(O)2N(R y3a )-, -S-, -N(R y3 )-, -OC(OR y3 )(R y3a )-,-N(R y3 )C(O)N(R y3a )-, and -OC(O)N(R y3 )- may have one or more groups selected from the group consisting of these groups interspersed; -R y1 and -R y1a These are independently -H, -T, and C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkinyls; Each T independently consists of phenyl, naphthyl, indenyl, indanyl, tetralinyl, and C. 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclils, 8-11 membered heterobicyclils, 8-30 membered carbopolycyclils, and 8-30 membered heteropolycyclils; Each-R y2These are, independently, halogen and C 1-6 Selected from the group consisting of alkyl groups; Each-R y3 ,-R y3a ,-R y4 ,-R y4a ,-R y5 ,-R y5a and -R y5b These are, independently of each other, -H and C 1-6 Selected from the group consisting of alkyl groups; C 1-6 Alkyl is optionally substituted with one or more identical or different halogens.

[0508] In certain embodiments, -L 2 - is C 1-20 It is an alkyl chain, which includes -O-, -T- and -C(O)N(R y1 )- may interrupt with one or more elements selected independently of this C 1-20 The alkyl chain consists of -OH, -T, and -C(O)N(R) y6 R y6a ) is optionally substituted with one or more elements independently selected from; where -R y1 ,-R y6 ,-R y6a H and C are independent of each other. 1-4 Selected from the group consisting of alkyl groups, T is phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 The group is selected from cycloalkyls, 3-10 member heterocyclils, 8-11 member heterobicyclils, 8-30 member carbopolycyclils, and 8-30 member heteropolycyclils.

[0509] In certain embodiments, -L 2 - has a molecular weight in the range of 14 g / mol to 750 g / mol.

[0510] In certain embodiments, -L 2 - has a chain length of 1 to 20 atoms.

[0511] Parts-L as used herein 2The term "chain length" in relation to -L 1 -L exists in the shortest bond between - and -Z 2 - Refers to the number of atoms.

[0512] In certain embodiments, -L 2 - is equation (i): [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates a connection to; Unmarked dashed lines indicate joining to -Z; -R 1 is -H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. It has, Here, part (i) of equation is sometimes further substituted.

[0513] In certain embodiments, -R of formula (i) 1 The is selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -R of formula (i) 1 is selected from the group consisting of -H, methyl, ethyl, and propyl. In certain embodiments, -R of formula (i) 1 is selected from the group consisting of -H and methyl. In certain embodiments, -R of formula (i) 1 It is methyl.

[0514] In a particular embodiment, n in formula (i) is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In a particular embodiment, n in formula (i) is selected from the group consisting of 0, 1, 2, 3, 4, and 5. In a particular embodiment, n in formula (i) is selected from the group consisting of 0, 1, 2, and 3. In a particular embodiment, n in formula (i) is selected from the group consisting of 0 and 1. In a particular embodiment, n in formula (i) is 0.

[0515] In certain embodiments, -L 2 -teeth, [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates a connection to; (Unmarked dashed lines indicate connections to -Z) It is a part selected from the group consisting of, Here, parts (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), and (xvii) are sometimes further substituted.

[0516] In certain embodiments, -L 2 -teeth, [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates a connection to; (Unmarked dashed lines indicate connections to -Z) It is selected from the group consisting of the following.

[0517] In certain embodiments, -L 2 -teeth, [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates a connection to; (Unmarked dashed lines indicate connections to -Z) It is selected from the group consisting of the following.

[0518] In certain embodiments, -L 2 - is expression (xvi): [ka] (In the formula, The dashed line with an asterisk indicates -L 1 - indicates a connection to; (Unmarked dashed lines indicate connections to -Z) It holds.

[0519] In certain embodiments, part-L 1 -L 2 -teeth, [ka] TIFF2026510974000040.tif46156 (in the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; (The dashed line with an asterisk indicates a connection to -Z.) It is selected from the group consisting of the following.

[0520] In certain embodiments, part-L 1 -L 2 - is equation (IId-ii): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; (The dashed line with an asterisk indicates a connection to -Z.) It holds.

[0521] In certain embodiments, part-L 1 -L 2 - is equation (IId-ii'): [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; (The dashed line with an asterisk indicates a connection to -Z.) It holds.

[0522] In certain embodiments, part-L 1 -L 2 -teeth, [ka] (In the formula, The unmarked dashed lines indicate the bonding of the CNP moiety, -D, to nitrogen through the formation of an amide bond; (The dashed line with an asterisk indicates a connection to -Z.) It is selected from the group consisting of the following.

[0523] In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of 5 to 200 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of 8 to 100 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of 10 to 80 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of 12 to 60 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of 15 to 40 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of about 20 kDa. In certain embodiments, -Z of formula (Ia) or (Ib) has a molecular weight of about 40 kDa.

[0524] The polymer portion -Z of formula (Ia) or (Ib) contains a polymer. In certain embodiments, -Z of formula (Ia) or (Ib) is 2-methacryloyloxyethyl phosphorylcholine derivatives, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(silicones) Anoacrylates, poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), Poly(hydroxypropyl oxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic acid-coglycolates), poly(methacrylamides), poly(methacrylates), poly(methyl oxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinyl The polymers include polymers selected from the group consisting of nylpyrrolidones, silicones, celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and their derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon polymers, xylans, and copolymers thereof.

[0525] In certain embodiments, -Z in formula (Ia) or (Ib) comprises a protein. Preferred proteins are selected from the group consisting of carboxyl-terminal peptides of chorionic gonadotropins described in US2012 / 0035101A1 (this document is incorporated herein by reference); albumin; XTEN sequences described in WO2011123813A2 (this document is incorporated herein by reference); proline / alanine random coil sequences described in WO2011 / 144756A1 (this document is incorporated herein by reference); proline / alanine / serine random coil sequences described in WO2008 / 155134A1 and WO2013 / 024049A1 (this document is incorporated herein by reference); and Fc fusion proteins.

[0526] In certain embodiments, -Z in formula (Ia) or (Ib) is polysarcosine. In certain embodiments, -Z in formula (Ia) or (Ib) contains poly(N-methylglycine). In certain embodiments, -Z in formula (Ia) or (Ib) contains a random coil protein moiety. In certain embodiments, -Z in formula (Ia) or (Ib) contains one random coil protein moiety. In certain embodiments, -Z in formula (Ia) or (Ib) contains two random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains three random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains four random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains five random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) contains six random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) comprises seven random coil protein moieties. In certain embodiments, -Z in formula (Ia) or (Ib) comprises eight random coil protein moieties.

[0527] In certain embodiments, such a random coil protein moiety contains at least 25 amino acid residues and up to 2000 amino acids. In certain embodiments, such a random coil protein moiety contains at least 30 amino acid residues and up to 1500 amino acid residues. In certain embodiments, such a random coil protein moiety contains at least 50 amino acid residues and up to 500 amino acid residues.

[0528] In certain embodiments, -Z in formula (Ia) or (Ib) includes a fatty acid derivative. In certain embodiments, -Z in formula (Ia) or (Ib) is a fatty acid derivative. In certain embodiments, -Z in formula (Ia) is a fatty acid derivative and x is 1.

[0529] In certain embodiments, -Z in formula (Ia) or (Ib) is a fatty acid derivative disclosed in WO 2006 / 097537 A2, which is incorporated herein by reference.

[0530] In certain embodiments, -Z of formula (Ia) or (Ib) comprises fatty acid derivatives disclosed in WO 2021 / 055497 A1, which is incorporated herein by reference. Therefore, in certain embodiments, -Z of formula (Ia) or (Ib) comprises the following structure (w): [ka] (In the formula, the dashed line represents -L in formula (Ia) or (Ib)) 2 - or -L 1 (Indicates a connection to -) It holds.

[0531] In a particular embodiment, -Z has the formula (w), and -L 1 - has equation (V).

[0532] In certain embodiments, -ZL 2 -L 1 - is the formula (wa): [ka] (In the formulas, the dashed line indicates the combination of formula (Ia) or (Ib) to -D.) It holds.

[0533] In a particular embodiment, the CNP is as follows: PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC (Sequence ID 98); PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Sequence ID 30); PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC (Sequence ID 99); and PGQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC (Sequence ID 100) It has a sequence selected from the group consisting of the following.

[0534] In a particular embodiment, CNP has a sequence selected from the group consisting of SEQ ID NO: 98, SEQ ID NO: 30, SEQ ID NO: 99, and SEQ ID NO: 100, -Z has formula (w), and -L 1 - is a reversible linker portion. In a particular embodiment, CNP has an sequence selected from the group consisting of SEQ ID NO: 98, SEQ ID NO: 30, SEQ ID NO: 99 and SEQ ID NO: 100, -Z has formula (w), and -L 1 - has formula (V). In a particular embodiment, CNP has a sequence selected from the group consisting of sequence number 98, sequence number 30, sequence number 99 and sequence number 100, and -ZL 2 -L 1 - has (wa). The above -L 1 - may be bonded to the CNP via lysine other than lysine in the ring structure, or -L 1 - may be attached to the N-terminus.

[0535] In certain embodiments, the CNP of SEQ ID NO: 98, SEQ ID NO: 30, SEQ ID NO: 99 and SEQ ID NO: 100 further comprises an acetyl group, for example, an acetyl group at the N-terminus of a peptide. In certain embodiments, the CNP of SEQ ID NO: 98, SEQ ID NO: 30, SEQ ID NO: 99 and SEQ ID NO: 100 further comprises an -OH or -NH2 group at the C-terminus. In certain embodiments, the CNP of SEQ ID NO: 98, SEQ ID NO: 30, SEQ ID NO: 99 and SEQ ID NO: 100 and -L 1 - is bonded to the remainder of the CNP ring portion, or to a portion other than the CNP portion.

[0536] In certain embodiments, -L 1 - is bound to lysine residues, such as the bolded lysine residues in SEQ ID NO: 98, SEQ ID NO: 30, SEQ ID NO: 99, and SEQ ID NO: 100.

[0537] [Table 1]

[0538] In a particular embodiment, the CNP is as follows:

[0539] [Table 2] It is selected from the group consisting of the following.

[0540] In certain embodiments, -Z in formula (Ia) or (Ib) is a hyaluronic acid-based polymer.

[0541] In certain embodiments, -Z in formula (Ia) or (Ib) is a polymer portion disclosed in WO 2013 / 024047 A1, which is incorporated herein by reference.

[0542] In certain embodiments, -Z in formula (Ia) or (Ib) is a polymer portion disclosed in WO 2013 / 024048 A1, which is incorporated herein by reference.

[0543] In certain embodiments, -Z in formula (Ia) or (Ib) is a PEG-based polymer. In certain embodiments, -Z is a branched or multi-armed PEG-based polymer.

[0544] In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 1, 2, 3, 4, 5, or 6 branch points. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 1, 2, or 3 branch points. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 1 branch point. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 2 branch points. In certain embodiments, -Z in formula (Ia) or (Ib) is a branched polymer having 3 branch points.

[0545] In certain embodiments, the branch point is selected from the group consisting of -N<, -CH<, and >C<.

[0546] In certain embodiments, such branching portion -Z of formula (Ia) or (Ib) is PEG-based.

[0547] In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of 5 kDa to 500 kDa. In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of 10 kDa to 250 kDa. In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of 10 kDa to 150 kDa. In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of 12 kDa to 100 kDa. In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of 15 kDa to 80 kDa. In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of 10 kDa to 80 kDa. In certain embodiments, the molecular weight is about 10 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 20 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 30 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 40 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 50 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 60 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 70 kDa. In certain embodiments, the molecular weight of such branched portion-Z of formula (Ia) or (Ib) is about 80 kDa. In certain embodiments, such branched portion-Z of formula (Ia) or (Ib) has a molecular weight of approximately 40 kDa.

[0548] In a particular embodiment, -Z is the following part: [ka] Includes.

[0549] In certain embodiments, -Z includes an amide bond.

[0550] In certain embodiments, -Z in formula (Ia) or (Ib) is the part of formula (a) below: [ka] (In the formula, The dashed line is -L 2 - or - indicates a bond to the remainder of Z; BP a is a branch point selected from the group consisting of -N<, -CR<, and >C<; -R is -H and C 1-6 Selected from the group consisting of alkyl groups; a is BP a If -N < or -CR <, then it is 0, and a is BP a If >C< then it is 1; -S a -, -S a' -, -S a'' -and-S a''' - is either a chemical bond or C, independently of each other. 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkynnyls; C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2)- may have one or more groups selected from the group consisting of these groups interspersed; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls; where each -T- is independently one or more identical or different -R 1 It is sometimes replaced by; Each-R 1 These are, independently, halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R 3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups; where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens; Each-R 2 ,-R2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens; -P a' , -P a" and -P a''' (This is independently a polymer part.) Includes.

[0551] In some cases, the part of formula (a) is replaced by one or more substituents.

[0552] In a particular embodiment, the BP of formula (a) a is -N <. In a particular embodiment, BP of equation (a) a is -CR<. In certain embodiments, -R is -H.

[0553] Therefore, in a particular embodiment, a in equation (a) is 0.

[0554] In a particular embodiment, the BP of formula (a) a is >C<.

[0555] In certain embodiments, the -S of formula (a) a - represents a chemical bond.

[0556] In a particular embodiment, -S of formula (a) a - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4)-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- and one or more chemical groups selected from the group consisting of -R may be inserted; where -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may include one or more chemical groups selected from the group consisting of ).

[0557] In certain embodiments, -S of formula (a) a' It is a chemical bond.

[0558] In a particular embodiment, -S of formula (a) a' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4)- and one or more chemical groups selected from the group consisting of -R may be inserted; where -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may include one or more chemical groups selected from the group consisting of ).

[0559] In a particular embodiment, -S of formula (a) a'' - represents a chemical bond.

[0560] In a particular embodiment, -S of formula (a) a'' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- and one or more chemical groups selected from the group consisting of -R may be inserted; where -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a"- is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may include one or more chemical groups selected from the group consisting of ).

[0561] In a particular embodiment, -S of formula (a) a''' - represents a chemical bond.

[0562] In a particular embodiment, -S of formula (a) a''' - is C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Selected from the group consisting of alkynnyl, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkinyls include -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 4 )-,-S(O)2N(R 4 )-,-S(O)N(R 4 )-, -S(O)2-, -S(O)-, -N(R 4 )S(O)2N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-,-N(R 4 )C(O)N(R 4a )-, and -OC(O)N(R 4 )- and one or more chemical groups selected from the group consisting of -R may be inserted; where -R 4 and -R 4a The is independently selected from the group consisting of -H, methyl, ethyl, propyl, and butyl. In certain embodiments, the -S of formula (a) a''' - is selected from the group consisting of methyl, ethyl, propyl, and butyl, and these include -O-, -C(O)- and -C(O)N(R 4 )- may include one or more chemical groups selected from the group consisting of ).

[0563] In a particular embodiment, -P of formula (a) a' , -Pa'' and -P a''' These are independently 2-methacryloyloxyethyl phosphorylcholines, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy)polymers, poly(amides), poly(amideamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethyl Poly(acrylamides), poly(esters), poly(ethylenes), poly(ethylene glycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyl oxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl oxazolines), poly(hydroxymethacrylates), poly(hydroxypropyl methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyl o Xazolines, poly(iminocarbonates), poly(lactic acids), poly(lactic acid-coglycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(orthoesters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinylamines), poly(vinyl methyl ethers), poly(vinylpyrrolidones) The polymers include polymers selected from the group consisting of (similar to), silicones, celluloses, carbomethylcelluloses, hydroxypropylmethylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and their derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other hydrocarbon polymers, xylans, and copolymers thereof.

[0564] In a particular embodiment, -P of formula (a) a' , -P a'' and -Pa''' These molecules independently have molecular weights of 5 kDa to 50 kDa, 5 kDa to 40 kDa in certain embodiments, 7.5 kDa to 35 kDa in certain embodiments, 7.5 to 30 kDa in certain embodiments, and 10 to 30 kDa in certain embodiments.

[0565] In a particular embodiment, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 7.5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 10 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 12.5 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 15 kDa. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' It has a molecular weight of approximately 20 kDa.

[0566] In a particular embodiment, -P of formula (a) a' , -P a'' and -P a''' It independently includes a PEG-based portion. In certain embodiments, the -P of formula (a) a' , -P a'' and -P a'''It independently includes a PEG-based portion comprising at least 20% PEG, at least 30% PEG in a particular embodiment, at least 40% PEG in a particular embodiment, at least 50% PEG in a particular embodiment, at least 60% PEG in a particular embodiment, at least 70% PEG in a particular embodiment, at least 80% PEG in a particular embodiment, and at least 90% PEG in a particular embodiment.

[0567] In a particular embodiment, -P of formula (a) a' , -P a'' and -P a''' It independently comprises a protein moiety, a random coil protein moiety in a particular embodiment, and a random coil protein moiety selected from the group consisting of PA, PAS, PAG, PG, and XTEN moieties in a particular embodiment.

[0568] In a particular embodiment, -P of formula (a) a' , -P a'' and -P a''' This is the PA portion. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' This is the PAS portion. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' This is the PAG portion. In certain embodiments, -P of formula (a) a' , -P a'' and -P a''' This is the PG portion. In a particular embodiment, -P of formula (a) a' , -P a'' and -P a''' This is the XTEN part.

[0569] In a particular embodiment, -Z includes one part of formula (a). In a particular embodiment, -Z includes two parts of formula (a). In another embodiment, -Z includes three parts of formula (a). In a particular embodiment, -Z includes four parts of formula (a). In a particular embodiment, -Z includes five parts of formula (a). In a particular embodiment, -Z includes six parts of formula (a).

[0570] In a particular embodiment, -Z is part of equation (b): [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z; b1 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; b2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; b3 is an integer between 150 and 1000; in certain embodiments, an integer between 150 and 500; in certain embodiments, an integer between 200 and 460; b4 is an integer between 150 and 1000; in certain embodiments, an integer between 150 and 500; in certain embodiments, an integer between 200 and 460. Includes.

[0571] In some cases, the part of formula (b) is substituted with one or more substituents.

[0572] In certain embodiments, b3 and b4 in formula (b) are the same integer. In certain embodiments, b3 and b4 in formula (b) are both integers between 200 and 250, and in certain embodiments, b3 and b4 in formula (b) are approximately 225. In certain embodiments, b3 and b4 in formula (b) are both integers between 400 and 500, and in certain embodiments, b3 and b4 in formula (b) are approximately 450.

[0573] In a particular embodiment, b1 in formula (b) is selected from the group consisting of 0, 1, 2, 3, and 4. In a particular embodiment, b1 in formula (b) is selected from the group consisting of 1, 2, and 3. In a particular embodiment, b1 in formula (b) is 2.

[0574] In a particular embodiment, b2 in formula (b) is selected from the group consisting of 1, 2, 3, 4, and 5. In a particular embodiment, b2 in formula (b) is selected from the group consisting of 2, 3, and 4. In a particular embodiment, b2 in formula (b) is 3.

[0575] In a particular embodiment, b1 in formula (b) is 2, b2 in formula (b) is 3, and b3 and b4 are both about 450. In a particular embodiment, b1 in formula (b) is 2, b2 in formula (b) is 3, and b3 and b4 are both about 225.

[0576] In certain embodiments, -Z includes one part of formula(b). In certain embodiments, -Z includes two parts of formula(b). In certain embodiments, -Z includes three parts of formula(b). In certain embodiments, -Z includes four parts of formula(b). In certain embodiments, -Z includes five parts of formula(b). In certain embodiments, -Z includes six parts of formula(b).

[0577] In a particular embodiment, -Z is part of equation (c): [ka] (In the formula, The dashed line is -L 2 - Indicates a bond to the remainder of -Z; c1 and c2 are independently integers between 150 and 500; in certain embodiments, they are integers between 200 and 460. Includes.

[0578] In some cases, the part of formula (c) is substituted with one or more substituents.

[0579] In a particular embodiment, c1 and c2 in equation (c) are both the same integer.

[0580] In certain embodiments, c1 and c2 of formula (c) are between 200 and 250, and in certain embodiments, they are about 225. In certain embodiments, c1 and c2 of formula (c) are between 400 and 500, and in certain embodiments, c1 and c2 of formula (c) are about 450.

[0581] In a particular embodiment, portion -Z is a branched PEG-based polymer containing at least 10% PEG, having one branch point and two PEG-based polymer arms, and having a molecular weight of about 40 kDa. Thus, each of the two PEG-based polymer arms has a molecular weight of about 20 kDa. In a particular embodiment, the branch point is -CH<.

[0582] In certain embodiments, -Z includes one part of formula(c). In certain embodiments, -Z includes two parts of formula(c). In certain embodiments, -Z includes three parts of formula(c). In certain embodiments, -Z includes four parts of formula(c). In certain embodiments, -Z includes five parts of formula(c). In certain embodiments, -Z includes six parts of formula(c).

[0583] In a particular embodiment, part-Z is equation (d): [ka] (In the formula, The dashed line is -L 2 - indicates a connection to; -Z b - is C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkinyls; here C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2 )- may have one or more groups selected from the group consisting of these groups interspersed; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls; where each -T- is independently one or more identical or different -R 1 It is sometimes replaced by; Each-R 1 These are, independently, halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(R 3 R 3a ), -S(O)2N(R 3 R 3a ), -S(O)N(R 3 R 3a ), -S(O)2R 3 ,-S(O)R 3 , -N(R 3 )S(O)2N(R 3a R 3b ), -SR 3 , -N(R 3 R 3a ), -NO2, -OC(O)R 3 , -N(R3 )C(O)R 3a , -N(R 3 )S(O)2R 3a , -N(R 3 )S(O)R 3a , -N(R 3 )C(O)OR 3a , -N(R 3 )C(O)N(R 3a R 3b ), -OC(O)N(R 3 R 3a ), and C 1-6 Selected from the group consisting of alkyl groups; where C 1-6 The alkyl group may be substituted with one or more identical or different halogens; Each-R 2 ,-R 2a ,-R 3 ,-R 3a and -R 3b These are independently -H and C 1-6 Selected from the group consisting of alkyl groups, where C 1-6 Alkyl is optionally substituted with one or more identical or different halogens; -Z a teeth, [ka] [In the formula, BP a , -S a -, -S a' -, -S a'' -, -S a''' -, -P a' , -P a'' , -P a''' And a are used as defined for formula (a). (is) It holds.

[0584] In some cases, the part of formula (d) is replaced by one or more substituents.

[0585] In a particular embodiment, the BP of formula (d) a , -S a -, -S a' -, -Sa'' -, -S a''' -, -P a' , -P a'' , -P a''' The definition of equation (a) is as described above.

[0586] In certain embodiments, -Z of equation (d) a The formula has formula (b). In a particular embodiment, b1, b2, b3, and b4 are as described for formula (b).

[0587] In certain embodiments, part-Z of formula (Ia) or (Ib) is formula (e): [ka] (In the formula, The dashed line is -L 2 - indicates a connection to; e is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15; -Z a teeth, [ka] [In the formula, b1, b2, b3, and b4 are used as defined for formula (b). (is) It holds.

[0588] In some cases, the part of formula (e) is replaced by one or more substituents.

[0589] In a particular embodiment, b1, b2, b3, and b4 of formula (e) are as defined above for formula (b).

[0590] In a particular embodiment, e in formula (e) is 1. In a particular embodiment, e in formula (e) is 2. In a particular embodiment, e in formula (e) is 3. In a particular embodiment, e in formula (e) is 4. In a particular embodiment, e in formula (e) is 5. In a particular embodiment, e in formula (e) is 6. In a particular embodiment, e in formula (e) is 7. In a particular embodiment, e in formula (e) is 8. In a particular embodiment, e in formula (e) is 9. In a particular embodiment, e in formula (e) is 10. In a particular embodiment, e in formula (e) is 11. In a particular embodiment, e in formula (e) is 12. In a particular embodiment, e in formula (e) is 13. In a particular embodiment, e in formula (e) is 14. In a particular embodiment, e in formula (e) is 15.

[0591] In a particular embodiment, e in formula (e) is selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, and 9. In a particular embodiment, e in formula (e) is selected from 3, 4, 5, and 6. In a particular embodiment, e in formula (e) is 5.

[0592] In a particular embodiment, e in formula (e) is 5, b1 in formula (e) is 2, b2 in formula (e) is 3, and b3 and b4 in formula (e) are both approximately 450.

[0593] In certain embodiments, part -Z of formula (Ia) or (Ib) is formula (ei) or (e-i'): [ka] (In the formula, The dashed line is -L 2 - indicates binding to e is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15; -Z a teeth, [ka] [In the formula, b1, b2, b3, and b4 are used as defined for formula (b). (is) It holds.

[0594] In certain embodiments, b1, b2, b3, and b4 of formulas (ei) and (e-i') are as defined above for formula (b). In certain embodiments, e of formulas (ei) and (e-i') is as described for formula (e). In certain embodiments, b1 of formulas (ei) and (e-i') is 2, b2 of formulas (ei) and (e-i') is 3, and b3 and b4 of formulas (ei) and (e-i') are both approximately 450.

[0595] In certain embodiments, -Z in formula (Ia) or (Ib) has formula (ei).

[0596] In a particular embodiment, part-Z is a branched PEG-based polymer containing at least 10% PEG, having three branching points and four PEG-based polymer arms, and having a molecular weight of about 40 kDa. Thus, each of the four PEG-based polymer arms has a molecular weight of about 10 kDa. In a particular embodiment, each of the three branching points is -CH<.

[0597] In a particular embodiment, part-Z is given by equation (f): [ka] (In the formula, The dashed line is -L 2 - indicates a connection to; BP f is a branch point selected from the group consisting of -N<, -CR<, and >C<; -R is -H and C 1-6 Selected from the group consisting of alkyl groups; f is BP f If -N< or -CR<, then it is 0, and f is BP f If >C< then it is 1; -S f-, -S f' -, -S f'' -and-S f''' - is either independently a chemical bond, or independently C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Selected from the group consisting of alkinyls; here C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkinyl is one or more identical or different -R 1 In some cases, it is replaced by C 1-50 Alkyl, C 2-50 Alkenyl and C 2-50 Alkynnyls include -T-, -C(O)O-, -O-, -C(O)-, and -C(O)N(R) 2 )-,-S(O)2N(R 2 )-,-S(O)N(R 2 )-, -S(O)2-, -S(O)-, -N(R 2 )S(O)2N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,-N(R 2 )C(O)N(R 2a )-, and -OC(O)N(R 2 )- may have one or more groups selected from the group consisting of these groups interspersed; Each -T- is independently phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 Selected from the group consisting of cycloalkyls, 3-10 membered heterocyclyls, 8-11 membered heterobicyclyls, 8-30 membered carbopolycyclyls, and 8-30 membered heteropolycyclyls; where each -T- is independently one or more identical or different -R 1 It is sometimes replaced by; Each R 1 These are, independently, halogen, -CN, oxo (=O), and -COOR. 3 , -OR 3 , -C(O)R 3 ,-C(O)N(...

Claims

1. An NPR-B agonist for use in the treatment of thoracolumbar malformations in human subjects with chondrodysplasia, such as thoracolumbar kyphosis, in subjects who have or are at risk of developing such malformations.

2. An NPR-B agonist for use according to claim 1, wherein the use is for the treatment of thoracolumbar kyphosis in the human subject.

3. An NPR-B agonist for use according to claim 1 or 2, wherein the use comprises the step of measuring spinal malformations before, and optionally during and / or after, the treatment.

4. An NPR-B agonist for use according to any one of claims 1 to 3, wherein the use comprises the step of continuously administering the NPR-B agonist to the subject, for example, daily, weekly, bi-weekly, or monthly, over a treatment period of at least about six months or at least about one year.

5. An NPR-B agonist for use according to any one of claims 1 to 4, wherein the use includes the step of measuring thoracolumbar malformations approximately every three months, or every six months, or every nine months, or every year, before the treatment and / or during the treatment or treatment period.

6. An NPR-B agonist for use according to any one of claims 1 to 5, wherein the use includes the step of measuring the degree of thoracolumbar kyphosis in the subject before, and optionally during and / or after, the treatment.

7. An NPR-B agonist for use according to any one of claims 1 to 6, wherein the use further comprises the step of measuring the degree of lordosis in the subject, for example, the degree of lumbar lordosis, before, and optionally during and / or after, the treatment.

8. An NPR-B agonist for use according to any one of claims 1 to 7, wherein the use is for the treatment of vertebral morphological malformations, such as thoracolumbar malformations including gibbs malformation, and the treatment results in an improvement in vertebral morphology.

9. The use of the NPR-B agonist for use according to any one of claims 1 to 8, further comprising the step of measuring vertebral morphology, for example, using vertebral morphometry, for example, point morphometry, of one or more vertebrae, for example, thoracic and / or lumbar vertebrae, for example, vertebral L1 and / or L2, before and during the treatment period, and optionally the treatment results in a decrease in the PH / MW ratio of vertebral L1 and / or L2.

10. An NPR-B agonist for use according to any one of claims 1 to 9, wherein the use results in a reduction or normalization of plaque malformations, such as plaque malformations of vertebral L1, L2, or L1 and L2.

11. An NPR-B agonist for use according to any one of claims 1 to 10, wherein the use results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, for example, the Cobb angle of thoracolumbar kyphosis measured between vertebral T10–L2, T11–L2, or T12–L2.

12. An NPR-B agonist for use according to any one of claims 1 to 11, wherein, prior to the use or treatment, the subject has a Cobb angle of thoracolumbar kyphosis exceeding approximately 20°, or approximately 25°, or approximately 30°, or approximately 35°, or approximately 40°, or approximately 45°, or approximately 50°.

13. An NPR-B agonist for use according to any one of claims 1 to 12, wherein the use results in a reduction or normalization of the Cobb angle of thoracolumbar kyphosis, for example by at least 3°, over a treatment period of at least about 6 months or at least about 12 months; or results in a reduction of the Z score associated with chondrodysplasia thoracolumbar kyphosis or a reduction of the Z score for healthy thoracolumbar kyphosis.

14. An NPR-B agonist for use according to any one of claims 1 to 13, wherein the use includes the step of measuring the thoracolumbar malformation using spinal radiography, e.g., lateral spinal radiography, before and / or during the treatment, and optionally the spinal radiography is taken while the subject is standing, sitting, or supine, or obtained from images or radiographs taken while the subject is standing, sitting, or supine.

15. An NPR-B agonist for use according to any one of claims 1 to 14, wherein the use is for the treatment of thoracolumbar malformations in a subject that is a child (i.e., a pediatric subject), for example, a child aged 0 to 18 years, for example, a child aged 0 to 14 years, for example, a child under 12 years, for example, a child under 10 years, or a child under 8 years, or a child under 6 years, for example, a child under 5 years.

16. An NPR-B agonist for use according to any one of claims 1 to 15, wherein the use is for the treatment of thoracolumbar malformations in subjects having epiphyseal openings, before and during treatment or the treatment period.

17. An NPR-B agonist for use according to any one of claims 1 to 16, wherein the use is for the treatment of unfixed thoracolumbar kyphosis.

18. An NPR-B agonist for use according to any one of claims 1 to 14, wherein the use is for the treatment of a subject having closed apophysitis.

19. An NPR-B agonist for use according to any one of claims 1 to 14 or claim 18, wherein the use is for the treatment of a subject who is at least 18 years old, for example, at least 25 years old, for example, at least 30 years old.

20. An NPR-B agonist for use according to any one of claims 1 to 16, 18, or 19, wherein the use is for the treatment of fixed thoracolumbar kyphosis.

21. An NPR-B agonist for use according to any one of claims 1 to 20, wherein the use is to increase height rate, for example, annual growth rate (AGV) or linear growth rate in the subject, or chondrodysplasia-related height Z score.

22. The aforementioned use is for further use in increasing the muscle function or physical function of the subject, for example, a) Increase in skeletal muscle strength, b) Increased skeletal muscle tone, c) Increase in skeletal muscle stamina, d) Increase in skeletal muscle mass, e) Reduction of skeletal muscle fatigue, f) Increase in cardiovascular endurance, g) Increased cardiovascular health, h) Reduced exercise intolerance, i) Increase in athletic ability, j) Reduction of exercise-induced fatigue, and k) Decreased muscle tone An NPR-B agonist for use according to any one of claims 1 to 21, for use in one or more of the following:

23. An NPR-B agonist for use according to any one of claims 1 to 22, wherein the use is for or may be for enhancing the physical function or daily living function of the subject, and may be assessed via one or more of (i) ACEM-OSM, (ii) ACEM-Physical Function, (iii) ACEM-Daily Living Function, and (iv) SF-10 Physical Function (the subject may be at least 4 years old, e.g., at least 5 years old).

24. An NPR-B agonist for use according to any one of claims 1 to 23, wherein the use further comprises the use of a spinal support or orthosis, such as a thoracolumbosacral orthosis (TLSO), before, during, or after the treatment / treatment period.

25. An NPR-B agonist for use according to any one of claims 1 to 24, wherein the NPR-B agonist is or comprises C-type natriuretic peptide (CNP), CNP conjugate, or CNP prodrug, or a pharmaceutically acceptable salt thereof.

26. An NPR-B agonist for use according to any one of claims 1 to 25, wherein the NPR-B agonist is a compound of formula (IIf'), a compound of formula (Iif), nabepeglitide, compound (1), or a pharmaceutically acceptable salt thereof, and the NPR-B agonist is optionally administered once weekly.

27. An NPR-B agonist for use according to any one of claims 1 to 25, wherein the NPR-B agonist is or comprises vosolitide (SEQ ID NO: 30), and the NPR-B agonist is optionally administered daily.

28. An NPR-B agonist for use according to any one of claims 1 to 27, wherein the subject has or has been diagnosed with developmental delay, e.g., developmental motor delay, and / or cranial abnormalities, e.g., foramen stenosis or foramen compression.

29. An NPR-B agonist for use according to any one of claims 1 to 28, wherein the use further comprises the use of an NPR-B agonist as described in any one of items C1 to C33.

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