GLP-2 analogues and GLP-2 peptibodies for administration before, during or after surgery - Patent Application 20070122999

Abstract

To provide methods of preventing or treating short bowel syndrome.SOLUTION: GLP-2 analogs, such as teduglutide, and fusion proteins of GLP-2 with immunoglobulin are administered before, during or after surgery, particularly resection of the small intestine. When short bowel syndrome develops after surgical resection of the small intestine, parenteral nutrition is usually necessary to compensate for reduced absorption of water and nutrients across the small intestine. GLP-2 analogs and GLP-2 fusion proteins promote growth of small intestine, improve nutrient absorption, and can reduce the need for parenteral nutrition after surgery.SELECTED DRAWING: Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62 / 582,055, filed November 6, 2017, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] The estimated prevalence of patients with short bowel syndrome (SBS) with nonmalignant diseases requiring home parenteral nutrition (HPN) is at least 40 per million people in the United States. SBS typically results from surgical resection of part or most of the small intestine due to conditions such as Crohn's disease, intestinal infarction, volvulus, trauma, congenital anomalies, and multiple strictures resulting from adhesions or radiation. Surgical resection may also involve removal of all or part of the colon. Patients with SBS suffer from malabsorption, which can lead to malnutrition, dehydration, and weight loss. Some patients are able to maintain protein and energy balance through increased appetite, and more rarely, they can become independent of parenteral fluids by maintaining their fluid and electrolyte requirements.

[0003] Post-translational processing of proglucagon produces glucagon-like peptide-2 (GLP-2), a 33-amino acid enterotrophic peptide hormone. GLP-2 acts to slow gastric emptying, reduce gastric secretion, and increase intestinal blood flow. GLP-2 also stimulates growth of the large and small intestine by increasing the proliferation of intestinal crypt cells and increasing the length of the intestinal villi, at least to increase the surface area of ​​the mucosal epithelium.

[0004] These effects suggest that GLP-2 can be used to treat various gastrointestinal conditions. Due to the demonstrated specific efficacy of GLP-2 in the small intestine, there has been much interest in the use of GLP-2 in the treatment of intestinal disease or injury (Non-Patent Document 1). Furthermore, GLP-2 has been shown to prevent or attenuate mucosal epithelial damage in a wide variety of preclinical models of gastrointestinal injury, including chemotherapy-induced mucositis, ischemia-reperfusion injury, dextran sulfate-induced colitis, and genetic models of inflammatory bowel disease (Non-Patent Document 1).

[0005] GLP-2 has a short half-life, limiting its therapeutic use because rapid in vivo cleavage of GLP-2 by dipeptidyl peptidase IV (DPP-IV) generates an essentially inactive peptide. The GLP-2 therapeutic teduglutide has a significantly extended half-life due to the substitution of alanine-2 with glycine. Teduglutide has shown promise as a therapeutic agent in the treatment of short bowel syndrome (SBS), which typically results from surgical resection of part or most of the small intestine for conditions such as Crohn's disease, intestinal infarction, intestinal volvulus, trauma, congenital anomalies, and multiple strictures resulting from adhesions or radiation. Surgical resection may also include resection of all or part of the colon. Patients with SBS suffer from malabsorption, which can lead to malnutrition, dehydration, and weight loss. While some patients may maintain protein and energy balance through increased appetite, maintaining fluid and electrolyte requirements to become parenteral fluid independent is even rarer.

[0006] SBS patients with a single-hole jejunostomy and no colon have low basal GLP-2 levels and limited meal-stimulated GLP-2 secretion due to removal of GLP-2-secreting L-cells, which are primarily located in the terminal ileum and colon. This GLP-2 deficiency results in minimal adaptive responses after resection and may also explain the gastric hypersecretion, rapid intestinal transit, and lack of intestinal adaptation seen in these SBS patients. Jeppesen et al. (Non-Patent Document 2) described the efficacy of pharmacological doses of native GLP-2 in SBS jejunostomy patients in an open-label study. Significant improvements in intestinal wet weight absorption and more modest improvements in energy absorption led to increases in body weight, lean body mass, and urinary creatinine excretion. In contrast, SBS patients with an intact colon have improved endogenous basal GLP-2 levels, resulting in an adaptive response to resection characterized by improved wet weight gain and energy absorption. The efficacy of additional pharmacological doses of GLP-2 receptor agonists in these patients is unclear and has not been studied. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Sinclair and Drucker,Physiology 2005:357-65 [Non-patent document 2] Gastroenterology 2001;120:806-815 Summary of the Invention [Problem to be solved by the invention]

[0008] There is a need to develop improved methods of administering GLP-2 analogs to treat SBS and other conditions resulting from surgical resection of the small intestine. [Means for solving the problem]

[0009] In one aspect, a method of treating a patient with short bowel syndrome following surgery is provided. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient within 48 hours of surgery. In some embodiments, the method comprises administering a GLP-2 peptibody to the patient within 48 hours of surgery. In some embodiments, the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO: 2. In some embodiments, the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO: 4. In some embodiments, the GLP-2 peptibody is administered subcutaneously to the patient at a dose of about 1.4 mg / kg, e.g., 1.4 mg / kg.

[0010] In some embodiments, the h(Gly2)GLP-2, GLP-2 analog and / or GLP-2 peptibody is administered to the patient 24 hours after surgery, 18 hours after surgery, 12 hours after surgery, 9 hours after surgery, 6 hours after surgery, 3 hours after surgery, 2 hours after surgery, or 1 hour after surgery. After surgery, the h(Gly2)GLP-2 or GLP-2 analog can be administered approximately every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours for 1, 2, 3, 4, 5, 6, or 7 days. Following surgery, the GLP-2 peptibody can be administered once in a subcutaneous or intravenous formulation. The GLP-2 peptibody can be administered again 3, 4, 5, 6, 7, or more days after the initial administration.

[0011] In some embodiments, the patient is receiving parenteral nutrition. The parenteral nutritional support may be short-term, medium-term, or long-term. See, for example, FIG. 6. In some embodiments, the patient receives a weekly amount of parenteral nutrition, and the method is effective in reducing the amount of parenteral nutrition the patient receives. In some embodiments, the method is effective in eliminating the need for the patient to receive parenteral nutrition. In some embodiments, the patient has short bowel syndrome secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, and ischemia.

[0012] In some embodiments, the patient is a) Limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals); b) fewer, but some detectable, GLP-2-producing tissues (compared to healthy individuals), and c) increased basal endogenous GLP-2 levels (compared to healthy individuals) It has one or more of the following.

[0013] In some embodiments, the method is effective to increase wet weight absorption in the intestinal tract, to enhance energy absorption in the intestinal tract, or to decrease wet weight of feces.

[0014] In another aspect, methods are provided for treating a patient undergoing surgery who is expected to develop short bowel syndrome after surgery. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient during surgery. In some embodiments, the h(Gly2)GLP-2 and / or GLP-2 peptibody is administered to the patient within 48 hours after surgery. In some embodiments, the methods include administering a GLP-2 peptibody to the patient within 48 hours after surgery. In some embodiments, the GLP-2 peptibody comprises any of the sequences set forth in SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO: 2. In some embodiments, the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO: 4. In some embodiments, the GLP-2 peptibody is administered subcutaneously to the patient at a dose of about 1.4 mg / kg, e.g., 1.4 mg / kg.

[0015] In some embodiments, the (Gly2)GLP-2, GLP-2 analog and / or GLP-2 peptibody is administered to the patient 24 hours after surgery, 18 hours after surgery, 12 hours after surgery, 9 hours after surgery, 6 hours after surgery, 3 hours after surgery, 2 hours after surgery, or 1 hour after surgery. After surgery, the h(Gly2)GLP-2 or GLP-2 analog can be administered approximately every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours for 1, 2, 3, 4, 5, 6, or 7 days. Following surgery, the GLP-2 peptibody can be administered once in a subcutaneous or intravenous formulation. The GLP-2 peptibody can be administered again 3, 4, 5, 6, 7, or more days after the initial administration.

[0016] In some embodiments, the patient is expected to receive parenteral nutrition after surgery. The parenteral nutritional support can be short-term, medium-term, or long-term. See, for example, FIG. 6. In some embodiments, the patient is expected to receive a certain amount of parenteral nutrition weekly, and the method is effective in reducing the amount of parenteral nutrition the patient receives. In some embodiments, the method is effective in eliminating the need for the patient to receive parenteral nutrition. In some embodiments, the patient has short bowel syndrome secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, and ischemia.

[0017] In some embodiments, the patient is a) Limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals); b) fewer, but some detectable, GLP-2-producing tissues (compared to healthy individuals), and c) increased basal endogenous GLP-2 levels (compared to healthy individuals) In some embodiments, the method is effective to increase wet weight absorption in the intestinal tract, to enhance energy absorption in the intestinal tract, or to decrease wet weight of feces.

[0018] In another aspect, a method of treating a patient predicted to develop short bowel syndrome after surgery is provided, comprising administering h(Gly2)GLP-2, a GLP-2 analog and / or a GLP-2 peptibody to the patient prior to surgery.

[0019] In some embodiments, a GLP-2 peptibody is administered to a patient. In some embodiments, the GLP-2 peptibody comprises any of the sequences set forth in SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO: 2. In some embodiments, the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO: 4. In some embodiments, the GLP-2 peptibody is administered subcutaneously to a patient at a dose of about 1.4 mg / kg, e.g., 1.4 mg / kg.

[0020] In some embodiments, h(Gly2)GLP-2 and / or a GLP-2 peptibody is administered to the patient at least once within one month prior to surgery. The h(Gly2)GLP-2 or GLP-2 analog can be administered once just prior to surgery: 24 hours, 18 hours, 12 hours, 9 hours, 6 hours, 3 hours, 2 hours, or 1 hour prior to surgery. Multiple doses of h(Gly2)GLP-2 or a GLP-2 analog can be administered every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours for 1, 2, 3, 4, 5, 6, or 7 days prior to surgery. The GLP-2 peptibody can be administered once subcutaneously or intravenously prior to surgery. The GLP-2 peptibody can be administered again 3, 4, 5, 6, 7, or more days after the initial administration.

[0021] In some embodiments, the patient is expected to receive parenteral nutrition after surgery. The parenteral nutritional support can be short-term, medium-term, or long-term. See, for example, FIG. 6. In some embodiments, the patient is expected to receive a certain amount of parenteral nutrition weekly, and the method is effective in reducing the amount of parenteral nutrition the patient receives. In some embodiments, the method is effective in eliminating the need for the patient to receive parenteral nutrition. In some embodiments, the patient is expected to develop short bowel syndrome after surgery secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, and ischemia.

[0022] In some embodiments, the patient is a) Limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals); b) fewer, but some detectable, GLP-2-producing tissues (compared to healthy individuals), and c) increased basal endogenous GLP-2 levels (compared to healthy individuals) It is expected that one or more of the following will occur after surgery.

[0023] Any of the above methods may be effective in increasing wet weight absorption in the intestinal tract, enhancing energy absorption in the intestinal tract, or reducing wet weight of feces. [Brief explanation of the drawings]

[0024] [Figure 1] Crypts and villi of the small intestine untreated (left panel) and treated with GLP-2 peptibody K274 (right panel). GLP-2 peptibody K274 has the amino acid sequence shown in SEQ ID NO:4. [Figure 2] Crypts and villi of the small intestine untreated (left panel) and treated with GLP-2 peptibody B264 (right panel). GLP-2 peptibody B264 has the amino acid sequence shown in SEQ ID NO:2. [Figure 3]Crypts and villi of the small intestine untreated (left panel) and treated with GLP-2[A2G], a h(Gly2)GLP-2 (right panel). [Figure 4] 1 shows the results of a histological study of the localization of GLP-2[A2G], which is h(Gly2)GLP-2, to the crypts and villi of the small intestine. [Figure 5] A and B are histological results of the localization of GLP-2 peptibody B264 (A) and GLP-2 peptibody K274 (B) to the crypts and villi of the small intestine. [Figure 6] Figure 1 shows three distinct stages of intestinal dysfunction that can occur after surgery, shown on the Y-axis and time on the X-axis. Administration of h(Gly2)GLP-2 (teduglutide) and / or GLP-2 peptibodies can promote intestinal growth over days or weeks, such as by increasing villus length and intestinal crypt depth. Such growth can improve intestinal absorption and reduce the need for parenteral nutrition (PN) support. DETAILED DESCRIPTION OF THE INVENTION

[0025] Described herein are methods for administering teduglutide, glucagon-like peptide (GLP-2) peptibodies, and other GLP-2 analogs before, during, or within a period of time after surgery. Generally, surgery refers to intestinal resections that may cause short bowel syndrome (SBS). Surgery may also include other procedures that may worsen SBS. The purpose of administering teduglutide, GLP-2 peptibodies, and GLP-2 analogs before, during, or within a period of time after surgery is to enhance intestinal absorption after surgery so as to reduce the amount of parenteral nutrition required. Parenteral nutritional support can be short-term, intermediate-term, or long-term. See, for example, Figure 6. Administration of GLP-2 peptibodies, teduglutide, or other GLP-2 analogs before or during surgery can avoid short-term parenteral nutrition or at least significantly shorten the duration for which short-term parenteral nutrition is required. Furthermore, postoperative administration of the GLP-2 peptibody, teduglutide, or other GLP-2 analogs may also shorten the duration of short- and medium-term parenteral nutrition requirements. Administration of the GLP-2 peptibody, teduglutide, or other GLP-2 analogs may reduce inflammation or increase the rate of small intestinal wound healing, thereby shortening the duration of short- and medium-term parenteral nutrition requirements. This method may avoid or minimize the complications of weaning a patient off parenteral nutrition.

[0026] Various methods are provided for treating patients with short bowel syndrome in which the colon is connected to the remaining small intestine by administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody before, during, or after surgery. Any of the h(Gly2)GLP-2, GLP-2 analog, and / or GLP-2 peptibody can be PEGylated, attached to PEG, or otherwise linked to PEG at one or more amino acids. The PEG can be of any molecular weight and degree of branching suitable for increasing the in vivo half-life of the h(Gly2)GLP-2, GLP-2 analog, or GLP-2 peptibody.

[0027] h(Gly2)GLP-2 contains the following peptide sequence: HGDGSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID NO: 1).

[0028] A GLP-2 peptibody can comprise GLP-2 fused to an Fc sequence or an albumin sequence. Exemplary GLP-2 peptibodies comprise one or more of the following:

[0029] a) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGGGGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK a GLP-2 peptibody comprising TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 2) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0030] b) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGGGGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT a GLP-2 peptibody comprising TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 3) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0031] c) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP a GLP-2 peptibody comprising ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0032] d) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE a GLP-2 peptibody comprising NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 5) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0033] e) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP a GLP-2 peptibody comprising PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 6) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0034] f) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGGGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ a GLP-2 peptibody comprising PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 7) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0035] g) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGAPGGGGGAAAAAGGGGGGAPGGGGGAAAAAGGGGGGAPGGGGGAAAAAGGGGGGAPDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT a GLP-2 peptibody comprising CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 8) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0036] h) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGGGGGGGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY a GLP-2 peptibody comprising KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 9) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0037] i) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN a GLP-2 peptibody comprising YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 10) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0038] j) a GLP-2 peptibody comprising the amino acid sequence (SEQ ID NO: 11) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0039] k) a GLP-2 peptibody comprising the amino acid sequence (SEQ ID NO: 12) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0040] l) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDGSAGSAAGSGEFDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN a GLP-2 peptibody comprising NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 13) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0041] m) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDAPAPAPAPAPAPAPAPAPAPDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG a GLP-2 peptibody comprising QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 14) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0042] n) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDAEAAAKEAAAKEAAAKALEAEAAAKEAAAKEAAAKADKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 15) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0043] o) Amino acid sequence HGDGSFSDEMNTILDNLAARDFINWLIQTKITDRGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP a GLP-2 peptibody comprising ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 16) or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to this amino acid sequence;

[0044] or any of the GLP-2 peptibody sequences described in U.S. Provisional Application No. 62 / 548,601, filed August 22, 2017.

[0045] In GLP-2 peptibodies, a linker sequence may be present between the GLP-2 sequence and other sequences, such as the Fc of IgG1 or human serum albumin. GLP-2 peptibody K274 has the amino acid sequence set forth in SEQ ID NO: 4. GLP-2 peptibody B264 has the amino acid sequence set forth in SEQ ID NO: 2.

[0046] GLP-2 peptibodies can be produced by processing a GLP-2 precursor polypeptide that contains a signal peptide directly linked to GLP-2. Any number of signal peptides may be used, and an exemplary signal peptide has the following sequence: METPAQLLFLLLWLPDTTG (SEQ ID NO: 17).

[0047] h(Gly2)GLP-2 is described in U.S. Patent No. 7,847,061, issued December 7, 2010. GLP-2 peptibodies are described in U.S. Provisional Application No. 62 / 548,601, filed August 22, 2017.

[0048] As used herein, the term "subcutaneous tissue" is defined as the layer of loose, irregular connective tissue immediately beneath the skin. For example, subcutaneous administration can be achieved by injecting the composition into areas including, but not limited to, the thigh, abdomen, buttocks, or scapular region. Subcutaneous administration can be achieved by injecting the composition using a syringe. However, other devices for administering formulations are also available, such as injection devices (e.g., Inject-ease™ and Genject™ devices), pen-type injectors (e.g., GenPen™), needleless devices (e.g., MediJector™ and BioJector™), and subcutaneous patch delivery systems.

[0049] As used in this application, the terms "about" and "approximately" are used synonymously. All numbers used in this application, with or without "about" or "approximately," are meant to encompass all normal variations understood by one of ordinary skill in the relevant art. As used herein, the term "about" or "approximately," when applied to one or more values ​​of interest, refers to a value similar to the indicated reference value. In certain embodiments, the term "about" or "approximately" refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of any indicated reference value (above or below), unless otherwise stated or otherwise apparent from the context (except where this number exceeds 100% of possible values).

[0050] As used herein, the terms "carrier" and "diluent" refer to pharmaceutically acceptable (e.g., safe and non-toxic for human administration) carriers or diluents useful in preparing pharmaceutical formulations. Typical diluents include sterile water, bacteriostatic water for injection (BWFI), pH buffer solutions (e.g., phosphate-buffered saline), sterile saline, Ringer's solution, or dextrose solution.

[0051] As used herein, the term "fusion protein" or "chimeric protein" refers to a protein produced by joining two or more originally separate proteins or portions thereof. In some embodiments, a linker or spacer can be present between each protein.

[0052] As used herein, the term "half-life" is the time it takes for a quantity, such as a protein concentration or activity, to decline to half of its initial measured value.

[0053] A "GLP-2 peptibody," "GLP-2 peptibody portion," or "GLP-2 peptibody fragment" and / or "GLP-2 peptibody variant," etc., can possess, mimic, or mimic at least one biological activity of at least one GLP-2 peptide, such as, but not limited to, ligand binding, in vitro, in situ, and / or preferably in vivo. For example, a suitable GLP-2 peptibody, specified portion, or variant may also modulate, enhance, alter, or activate signal transduction or other measurable or detectable activity of at least one GLP-2 receptor. GLP-2 peptibodies have suitable binding affinity for protein ligands, such as GLP-2 receptors, and may optionally have low toxicity. GLP-2 peptibodies can be used to treat patients long-term with good to very good symptom relief and low toxicity.

[0054] As used herein, the terms "improve," "increase," or "decrease," or grammatical equivalents, refer to a value relative to a baseline measurement, such as a measurement in the same individual prior to each initiation of a treatment described herein, or in a control patient (or patients) in the absence of a treatment described herein. A "control patient" is a subject suffering from the same disease form as the subject being treated and who is approximately the same age as the subject being treated.

[0055] As used herein, the term "in vitro" refers to phenomena that take place in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than inside a multicellular organism.

[0056] As used herein, the term "in vivo" refers to phenomena that occur within multicellular organisms, such as humans and non-human animals. In cell-based systems, the term may also be used to refer to phenomena that occur within living cells (as opposed to, for example, in a test tube).

[0057] As used herein, the term "linker" refers to an amino acid sequence in a fusion protein other than that found at a particular position in the native protein, and is generally designed to be flexible or to allow the insertion of a structure such as an α-helix between two protein moieties. A linker is also called a spacer. A linker or spacer typically has no biological functionality on its own.

[0058] As used herein, the term "PEG" includes any form of poly(ethylene glycol), including alkoxy PEG, bifunctional PEG, multi-arm PEG, branched PEG, branched PEG, pendant PEG (i.e., PEG or related polymers having one or more functional groups pendant to the polymer backbone), or PEG having internal degradable linkages.

[0059] As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally regarded as physiologically tolerable.

[0060] As used herein, the term "polypeptide" refers to a continuous chain of amino acids linked via peptide bonds. The term is used to refer to an amino acid chain of any length, but those skilled in the art will understand that the term is not limited to long chains and may refer to a minimal chain comprising two amino acids linked via peptide bonds. As known to those skilled in the art, polypeptides may be processed and / or modified. As used herein, the terms "polypeptide" and "peptide" are used interchangeably. The term "polypeptide" may also refer to a protein.

[0061] As used herein, the terms "prevent" or "prevention," when used in reference to the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder, and / or condition. See definition of "risk."

[0062] As used herein, the term "subject" refers to a human or any non-human animal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, a subject is a human. A subject may be a patient, which refers to a human who visits a healthcare provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be afflicted with or susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0063] As used herein, the term "substantially" refers to the qualitative state of exhibiting all or nearly all extent or degree of a characteristic or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, reach perfection and / or progress to perfection or achieve or approach a definite result. The term "substantially" is therefore used to express the potential lack of perfection inherent in many biological and chemical phenomena.

[0064] As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount sufficient to treat, diagnose, prevent, and / or delay the onset of symptoms of the disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. Those skilled in the art will appreciate that a therapeutically effective amount will typically be administered in a dosing regimen comprising at least one dose.

[0065] As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, or prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of, one or more symptoms or characteristics of a particular disease, injury, and / or condition. Treatment may also be administered to subjects who do not show signs of disease and / or who show only early signs of disease, with the intent of reducing the risk of developing pathology associated with the disease.

[0066] PEGylated GLP-2 A variety of useful active GLP-2 analogs and derivatives have been described in the literature, see U.S. Patent No. 5,789,379, issued June 20, 2000, WO 02 / 066511, published August 27, 2003, WO 99 / 43361, published October 14, 1999, WO 04 / 035624, published April 29, 2004, and WO 04 / 085471, published October 7, 2004. Any of these GLP-2 analogs and derivatives can be conjugated to PEG.

[0067] Serum half-life can also be extended by conjugating h(Gly2)GLP-2, GLP-2 analogs, or even GLP-2 peptibodies to polyethylene glycol (PEG) or other related polymers known in the art. Such PEGylation can increase molecular size and reduce the accessibility of surface and functional groups. These effects can increase plasma half-life, protect against protease degradation, reduce immunogenicity, and decrease hepatic uptake.

[0068] GLP-2 peptibody Exemplary GLP-2 peptibodies include, but are not limited to, those comprising the sequences of SEQ ID NOS: 2-16. Additionally, any of the above GLP-2 peptibody sequences may contain a C-terminal lysine (K). The GLP-2 sequence of a GLP-2 peptibody may also incorporate amino acid substitutions that confer peptide resistance to the endogenous enzyme dipeptidyl peptidase IV (DPP-IV). Such analogs preferably, but not necessarily, incorporate appropriate substitutions of the Ala2 residue with a genetically encoded amino acid to enable recombinant production of the desired protein. Useful amino acid substitutions for alanine-2 that can provide GLP-2 analogs that retain GLP-2 receptor agonist activity and are less susceptible to DPP-IV include Gly, d-Ala, Val, Glu, Lys, Arg, Leu, and Ile. Still other GLP-2 analogs include those in which Met-10 is replaced with an amino acid that is less susceptible to oxidation.

[0069] GLP-2 peptibodies, GLP-2 analogs, or even h(Gly2)GLP-2 can be derivatized to extend their blood half-life, for example, at internal or substituted lysines by conjugation with a lipophilic group, a polyethylene glycol group, the Fc region of an immunoglobulin, albumin, or any other functional group that has the desired effect of reducing the rate at which the peptide is endogenously degraded after administration. Such derivatized forms may also be derivatized GLP-2 analogs, which contain substitutions, such as conservative or non-conservative lysine substitutions, that have little adverse effect on GLP-2 receptor activity but allow for the attachment of desired functional groups. It will be understood that derivatized forms of GLP-2 or GLP-2 analogs are considered prodrugs, i.e., GLP-2 receptor agonists if they exert their endogenous effects via the GLP-2 receptor after administration, even if they do not exhibit GLP-2 receptor agonist properties in the form before administration.

[0070] In one aspect, a method of treating a patient with short bowel syndrome associated with a non-malignant disease is provided. The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery, using a dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives. In some embodiments, the GLP-2 peptibody comprises a sequence set forth in any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody is intended for use in the manufacture of a medicament for treating short bowel syndrome associated with a non-malignant disease immediately prior to surgery, during surgery, or within a period following surgery.

[0071] Some patients are able to maintain protein and energy balance through increased appetite, and in rare cases, maintaining fluid and electrolyte requirements can lead to parenteral fluid independence. Long-term parenteral nutrition (PN) is lifesaving for patients with intestinal failure, but it is expensive, impairs quality of life, and is associated with serious complications, such as catheter sepsis, venous obstruction, and liver failure. Total parenteral nutrition often causes small intestinal atrophy, which can increase PN dependence as the small intestine shrinks and absorbs less energy, water, and other nutrients. Therapies that enhance absolute intestinal absorption and eliminate or minimize the need for PN hold great promise for SBS patients. Administration of one or more of h(Gly2)GLP-2, GLP-2 analogs, and GLP-2 peptibodies before, during, or immediately after surgery can reduce the need for PN, reduce the amount of PN administered, shorten the duration of PN administration, or even avoid PN altogether.

[0072] Without wishing to be bound by theory, h(Gly2)GLP-2, GLP-2 analogs, and GLP-2 peptibodies have numerous activities, including slowing gastric emptying, reducing gastric secretion, improving intestinal blood flow, and stimulating growth of the small and large intestine. Growth of the small and large intestine may occur through stimulation of crypt cell proliferation and inhibition of intestinal epithelial cell apoptosis. Increased intestinal surface area may result in improved absorption of water, nutrients, and energy. Such improved absorption may reduce or even eliminate the need for parenteral nutrition.

[0073] An effective dosing regimen for treating SBS patients with a connected colon can involve delivering a selected GLP-2 receptor agonist to the patient for a time and at a dose sufficient to enhance intestinal absorption. One suitable treatment regimen calls for administration of h(Gly2)GLP-2 by subcutaneous injection into the abdomen, thigh, or arm once daily at a dose ranging from 30 to 150 μg / kg per day for approximately 21 days. h(Gly2)GLP-2 can be administered subcutaneously or intravenously.

[0074] GLP-2 peptibodies may also be administered subcutaneously or intravenously. GLP-2 peptibodies can be administered subcutaneously at a dose of 0.02 to 3.0 mg / kg once every 2 to 14 days. GLP-2 peptibodies can be administered subcutaneously at a dose of 0.02 to 3.0 mg / kg, 0.02 to 0.5 mg / kg, 0.04 to 0.45 mg / kg, 0.08 to 0.4 mg / kg, 0.10 to 0.35 mg / kg, 0.20 to 0.30 mg / kg, 0.02 to 0.05 mg / kg, 0.03 to 0.04 mg / kg, 0.05 to 0.10 mg / kg, 0.10 to 0.1 ... It may be administered subcutaneously according to a dosage regimen of 0.2-0.3 mg / kg, 0.3-0.4 mg / kg, 0.4-0.5 mg / kg, 0.5-0.8 mg / kg, 0.7-1.0 mg / kg, 0.9-1.2 mg / kg, 1.0-1.5 mg / kg, 1.2-1.8 mg / kg, 1.5-2.0 mg / kg, 1.7-2.5 mg / kg, or 2.0-3.0 mg / kg.

[0075] The administered GLP-2 peptibody may be at a concentration of 10-100 mg / mL, 10-90 mg / mL, 20-80 mg / mL, 25-75 mg / mL, 30-70 mg / mL, 50-100 mg / mL, 60-90 mg / mL, about 75 mg / mL, 75 mg / mL, 10-20 mg / mL, 15-25 mg / mL, 12-18 mg / mL, 13-17 mg / mL, 14-16 mg / mL, about 15 mg / mL, or 15 mg / mL.

[0076] The effect of administration of h(Gly2)GLP-2, GLP-2 analogs or GLP-2 peptibodies before, during or after surgery can be rapid, for example, within 60 hours, 48 ​​hours, 36 hours or 24 hours after administration. Such administration can rapidly increase GI (gastrointestinal) transit within 48 hours after surgery. Such administration can also increase stem cell activity and provide long-term improvement in small intestinal wound healing after surgery.

[0077] In some embodiments, administration of h(Gly2)GLP-2, a GLP-2 analog, or a GLP-2 peptibody can reduce inflammation due to surgery. For example, administration 2, 3, 4, 5, or 6 hours before surgery can reduce the inflammatory response due to small intestinal resection. Reduced inflammatory response can promote recovery from surgery and allow further administration of h(Gly2)GLP-2, a GLP-2 analog, or a GLP-2 peptibody to act more rapidly to enhance small and large intestinal growth, for example, by increasing crypt depth or increasing villus height.

[0078] In some embodiments for pre- and post-operative administration, the GLP-2 peptibody is administered subcutaneously at a dose of 0.02-0.5 mg / kg every 2-14 days. In some embodiments, the GLP-2 peptibody is administered intravenously at a dose of 0.02-3.0 mg / kg every 2-14 days. In some embodiments, the GLP-2 peptibody is administered at a concentration of 10-200 mg / mL.

[0079] Candidates for treatment include patients with short bowel syndrome who retain at least 50% or more of their colon connected to the remaining small intestine after surgery. Such candidates for treatment are identified herein as patients who have at least 50% of their colon connected after surgery. In another preferred embodiment, SBS patients with connected colon have or are expected to have at least about 50 cm of small intestine length after surgery, preferably, but not necessarily, incorporating at least a portion of the ileum.

[0080] In one aspect, a method of treating a patient with short bowel syndrome associated with or secondary to Crohn's disease is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has (or is expected to have after surgery) a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period after surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the compositions described herein are for use in a method for treating short bowel syndrome associated with or secondary to Crohn's disease, the method comprising administering a GLP-2 peptibody immediately prior to surgery, during surgery, or within a period following surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with or secondary to Crohn's disease. The medicament can be administered immediately prior to surgery, during surgery, or within a period following surgery.

[0081] In one aspect, a method of treating a patient with short bowel syndrome associated with intestinal infarction is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the compositions described herein are intended for use in a method of treating short bowel syndrome associated with intestinal infarction, the method comprising administering a GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with intestinal infarction. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0082] In one aspect, a method of treating a patient with short bowel syndrome associated with or secondary to intestinal volvulus is provided. The patient receives a weekly amount of parenteral nutrition or is expected to receive a weekly amount of parenteral nutrition after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period after surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the compositions described herein are for use in a method of treating short bowel syndrome associated with or secondary to volvulus, the method comprising administering a GLP-2 peptibody immediately prior to surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with or secondary to volvulus. The medicament can be administered immediately prior to surgery, during surgery, or within a period of time after surgery.

[0083] In one aspect, a method of treating a patient with short bowel syndrome associated with congenital intestinal anomalies is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period of time following surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the compositions described herein are intended for use in a method of treating short bowel syndrome associated with congenital intestinal anomalies, the method comprising administering a GLP-2 peptibody immediately prior to surgery, during surgery, or within a period of time following surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with congenital intestinal anomalies. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0084] In one aspect, a method is provided for treating a patient with short bowel syndrome associated with multiple strictures due to adhesions or radiation. The patient receives a weekly amount of parenteral nutrition or is expected to receive a weekly amount of parenteral nutrition after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for treating short bowel syndrome associated with multiple strictures due to adhesions or radiation, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with multiple strictures due to adhesions or radiation. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0085] In one aspect, a method of treating a patient with short bowel syndrome associated with or secondary to ischemia is provided. The patient receives a weekly amount of parenteral nutrition or is expected to receive a weekly amount of parenteral nutrition after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period after surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for treating short bowel syndrome associated with or secondary to ischemia, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with or secondary to ischemia. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0086] In one aspect, a method is provided for treating a patient with short bowel syndrome (SBS) associated with limited but detectable meal-stimulated GLP-2 secretion (compared to a healthy individual). The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to the remaining small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period after surgery. The dosing regimen is effective to enhance meal-stimulated GLP-2 secretion. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome associated with limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals), the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals). The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0087] In one aspect, a method of treating a patient with short bowel syndrome in which at least 25% of the colon is preserved in the remaining small intestine is provided. The patient receives a certain amount of parenteral nutrition weekly, or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in which at least 25% of the colon is preserved in the remaining small intestine, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in patients with a small intestine remnant that retains at least 25% of the colon. The medicament can be administered immediately before surgery, during surgery, or within a period following surgery.

[0088] In one aspect, a method is provided for treating a patient with short bowel syndrome (SBS) with reduced but still detectable GLP-2-producing tissue (compared to a healthy individual). The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to the remaining small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen is used that is effective to increase the amount of GLP-2-producing tissue in the patient. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient with short bowel syndrome who has fewer, but some detectable GLP-2-producing tissues (compared to healthy individuals), the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient with short bowel syndrome who has fewer, but some detectable GLP-2-producing tissues (compared to healthy individuals). The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0089] In one aspect, a method is provided for treating a patient with short bowel syndrome associated with elevated basal levels of endogenous GLP-2 (compared to a healthy individual). The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient with elevated basal endogenous GLP-2 levels (compared to healthy individuals), the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient with elevated basal endogenous GLP-2 levels (compared to healthy individuals). The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0090] In one aspect, methods are provided for treating a patient with short bowel syndrome who has similar or elevated endogenous meal-stimulated GLP-2 levels (compared to a healthy individual). The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to the remaining small intestine. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period after surgery. A dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient with increased meal-stimulated endogenous GLP-2 levels (compared to a healthy individual), the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient with increased meal-stimulated endogenous GLP-2 levels (compared to a healthy individual). The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0091] In one aspect, methods are provided for treating a patient with short bowel syndrome who has a connected colon and a remaining small intestine ranging from about 25 cm to about 200 cm. The patient receives a certain amount of parenteral nutrition weekly, or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody is intended for use in a method for treating short bowel syndrome in a patient having a connected colon and a remaining small intestine ranging from about 25 cm to about 200 cm, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time following surgery. In another embodiment, the GLP-2 peptibody is intended for use in the manufacture of a medicament for treating short bowel syndrome in a patient having a connected colon and a remaining small intestine ranging from about 25 cm to about 200 cm, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time following surgery. In another embodiment, the GLP-2 peptibody is intended for use in the manufacture of a medicament for treating short bowel syndrome in a patient having a connected colon and a remaining small intestine ranging from about 25 cm to about 200 cm. The medicament can be administered immediately before surgery, during surgery, or within a period of time following surgery.

[0092] In one aspect, a method is provided for treating a patient with short bowel syndrome who has endogenous GLP-2 levels in a fed state that are at least about 10% lower (compared to a healthy individual). The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period of time after surgery. A dosing regimen is used that is effective to increase the patient's endogenous GLP-2 levels in a fed state. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody is intended for use immediately prior to surgery, during surgery, or within a period of time after surgery in a method for treating short bowel syndrome in a patient who has endogenous GLP-2 levels in a fed state that are at least about 10% lower (compared to a healthy individual). In another embodiment, the GLP-2 peptibody is intended for use in the manufacture of a medicament for treating short bowel syndrome in patients with at least about 10% endogenous GLP-2 (compared to healthy individuals) in a fed state immediately prior to surgery, during surgery, or within a period following surgery. The drug can be administered immediately prior to surgery, during surgery, or within a period following surgery.

[0093] In one aspect, a method is provided for treating a patient with short bowel syndrome who has a connected colon and at least about 50 cm of remaining small intestine. The patient receives a certain amount of parenteral nutrition weekly, or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., resection of the small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period of time after surgery. A dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is intended for use immediately prior to surgery, during surgery, or within a period of time after surgery in a method for treating short bowel syndrome in a patient with a connected colon and at least about 50 cm of remaining small intestine. In another embodiment, the GLP-2 peptibody is intended for use in the manufacture of a medicament for treating short bowel syndrome in a patient with a connected colon and at least about 50 cm of remaining small intestine immediately prior to surgery, during surgery, or within a period of time following surgery. The medicament can be administered immediately prior to surgery, during surgery, or within a period of time following surgery.

[0094] In one aspect, a method for reducing the wet weight of feces in a patient with short bowel syndrome is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to a residual small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to reduce the wet weight of the patient's feces is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is intended for use in a method for reducing the wet weight of feces in a patient with short bowel syndrome, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for reducing fecal wet weight in patients with short bowel syndrome. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0095] The absolute amount of wet weight absorption can be obtained by subtracting the wet weight of the feces from the wet weight of the diet.

[0096] In one aspect, a method for increasing urine weight in a patient with short bowel syndrome is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestine resection. The patient also has a colon connected to a residual small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to increase the patient's urine weight is used. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is intended for use in a method for increasing urine weight in a patient expected to have short bowel syndrome after surgery, the method including administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for increasing urine weight in a patient with short bowel syndrome. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0097] In one aspect, a method of treating a patient with short bowel syndrome without inflammatory bowel disease is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestine resection. The patient also has a colon connected to a remnant small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is intended for use in a method of treating short bowel syndrome in a patient without inflammatory bowel disease, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome without inflammatory bowel disease. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0098] In one aspect, a method is provided for increasing intestinal crypt depth in a patient with short bowel syndrome and reduced intestinal crypt depth compared to a healthy individual. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method includes administering h(Gly2)GLP-2 and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period after surgery. A dosing regimen effective to increase intestinal crypt depth in the patient is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of increasing intestinal crypt depth in a patient with short bowel syndrome and reduced intestinal crypt depth compared to healthy individuals, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for increasing intestinal crypt depth in a patient with short bowel syndrome and reduced intestinal crypt depth compared to healthy individuals. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0099] In one aspect, a method is provided for increasing the number of mitotic figures per 100 intestinal crypt epithelial cells in a patient with short bowel syndrome and a reduced number of mitotic figures per 100 intestinal crypt epithelial cells compared to a healthy individual. The patient receives a weekly amount of parenteral nutrition or is expected to receive a weekly amount of parenteral nutrition after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method comprises administering h(Gly2)GLP-2, an AGLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period following surgery using a dosing regimen effective to increase the number of mitotic figures per 100 intestinal crypt epithelial cells in the patient. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of increasing the number of mitotic figures per 100 intestinal crypt epithelial cells in a patient with short bowel syndrome and a reduced number of mitotic figures per 100 intestinal crypt epithelial cells compared to healthy individuals, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for increasing the number of mitotic figures per 100 intestinal crypt epithelial cells in a patient with short bowel syndrome and a reduced number of mitotic figures per 100 intestinal crypt epithelial cells compared to healthy individuals.

[0100] Several physiological mechanisms may explain the observed benefits in intestinal absorption with teduglutide treatment. SBS patients with single-port jejunostomy who have limited or no meal-stimulated GLP-2 secretion often suffer from gastric hypersecretion and rapid gastric emptying, at least initially, after intestinal resection. GLP-2 has been shown to attenuate gastric acid secretion in sham-fed healthy individuals and prolong gastric emptying in SBS patients. Administration of h(Gly2)GLP-2, GLP-2 analogs, and / or GLP-2 peptibodies may also attenuate gastric acid secretion and prolong gastric emptying, as well as restore physiological feedback (previously referred to as the ileal brake mechanism). Supraphysiological doses of h(Gly2)GLP-2, GLP-2 analogs, or GLP-2 peptibodies may generate localized high concentrations that inhibit gastric secretion and induce small intestinal growth. Regardless of the precise physiological mechanism, enhanced intestinal absorption associated with treatments that improve intestinal adaptation will preferably translate into benefits related to body weight or body composition, hydration, physical activity, and ultimately quality of life.

[0101] In one aspect, a method is provided for restoring at least a portion of the ileal brake mechanism in a patient with short bowel syndrome and a reduced or absent ileal brake mechanism. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period after surgery. A dosing regimen is used that is effective to restore at least a portion of the ileal brake mechanism in the patient. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of restoring at least a portion of the ileal brake mechanism in a patient with short bowel syndrome and a reduced or absent ileal brake mechanism, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another aspect, the GLP-2 peptibody is for use in the manufacture of a medicament for restoring at least a portion of the ileal brake mechanism in a patient with short bowel syndrome and a reduced or absent ileal brake mechanism. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0102] In one aspect, a method is provided for attenuating gastric hypersecretion in a patient with short bowel syndrome and gastric hypersecretion. The patient receives a weekly amount of parenteral nutrition or is expected to receive a weekly amount of parenteral nutrition after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period after surgery. A dosing regimen effective to attenuate gastric hypersecretion is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of attenuating gastric hypersecretion in a patient with short bowel syndrome and gastric hypersecretion, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for attenuating gastric hypersecretion in a patient with short bowel syndrome and gastric hypersecretion. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0103] In one aspect, a method is provided for reducing rapid gastric emptying in a patient with short bowel syndrome and rapid gastric emptying. The patient receives a weekly dose of parenteral nutrition or is expected to receive a weekly dose of parenteral nutrition after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to reduce the rate of gastric emptying is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is intended for use in a method for reducing rapid gastric emptying in a patient with short bowel syndrome and rapid gastric emptying, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for attenuating rapid gastric emptying in a patient with short bowel syndrome and rapid gastric emptying. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0104] In one aspect, a method for reducing or inhibiting gastric secretion in a patient with short bowel syndrome is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to reduce or inhibit gastric secretion is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for reducing or inhibiting gastric secretion in a patient with short bowel syndrome, the method including administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for reducing or inhibiting gastric secretion in patients with short bowel syndrome. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0105] In one aspect, a method of inducing small intestinal growth in a patient with short bowel syndrome is provided. The patient receives a weekly amount of parenteral nutrition or is expected to receive a weekly amount of parenteral nutrition after surgery, e.g., small intestinal resection. The patient also has a colon connected to a remnant small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to induce small intestinal growth is used. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of inducing small intestinal growth in a patient with short bowel syndrome, the method including administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for inducing small intestinal growth in patients with short bowel syndrome. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0106] In one aspect, a method for increasing protein transport in a patient with short bowel syndrome is provided. The patient receives a certain amount of parenteral nutrition weekly or is expected to receive a certain amount of parenteral nutrition weekly after surgery, e.g., small intestinal resection. The patient also has a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately before surgery, during surgery, or within a period after surgery. A dosing regimen effective to increase protein transport in the patient is used. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for increasing protein transport in a patient with short bowel syndrome, the method including administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for increasing protein transport in patients with short bowel syndrome. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0107] In one aspect, a method is provided for reducing the incidence of dehydration in a patient with short bowel syndrome or expected to have short bowel syndrome after surgery, e.g., intestinal resection. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period of time after surgery. A dosing regimen is used that is effective to reduce the likelihood of dehydration in the patient. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for reducing the incidence of dehydration in a patient with short bowel syndrome, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for reducing the incidence of dehydration in a patient with short bowel syndrome. The drug can be administered immediately before surgery, during surgery, or within a period after surgery.

[0108] In one aspect, methods are provided for reducing the incidence of renal failure in a patient with short bowel syndrome or expected to have short bowel syndrome after surgery, e.g., intestinal resection. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen is used that is effective to reduce the likelihood of the patient developing renal failure. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for reducing the incidence of renal failure in a patient with short bowel syndrome, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period following surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for reducing the incidence of renal failure in a patient with short bowel syndrome. The drug can be administered immediately before surgery, during surgery, or within a period after surgery.

[0109] In one aspect, a method for reducing the incidence of kidney stones in a patient with short bowel syndrome or expected to develop short bowel syndrome after surgery, e.g., intestinal resection, is provided. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen is used that is effective to reduce the likelihood of the patient developing kidney stones. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for reducing the incidence of kidney stones in a patient with short bowel syndrome, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period following surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for reducing the incidence of kidney stones in a patient with short bowel syndrome. The drug can be administered immediately before surgery, during surgery, or within a period after surgery.

[0110] In one aspect, methods are provided for treating a patient with short bowel syndrome in which the colon is connected to the remaining small intestine, or a patient expected to have short bowel syndrome in which the colon is connected to the remaining small intestine following surgery, e.g., intestinal resection. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to enhance intestinal absorption by the patient is used. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody is for use in a method for treating short bowel syndrome in a patient in which the colon is connected to the remaining small intestine, the method including administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in patients with a colon connected to a remnant small intestine. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0111] In one aspect, a method is provided for treating a patient with short bowel syndrome (SBS) in which the colon is connected to the remaining small intestine, or a patient expected to have SBS in which the colon is connected to the remaining small intestine after surgery, e.g., intestinal resection. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to enhance intestinal absorption by the patient is used. h(Gly2)GLP-2 is administered intravenously at a daily dose of 0.04-0.06 mg / kg body weight, e.g., 0.05 mg / kg body weight. The GLP-2 peptibody is administered by subcutaneous injection into the patient's abdomen, thigh, or arm at a dose of 30-150 μg / kg. Daily administration is possible. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2 to 16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4.

[0112] In one aspect, a method is provided for treating a patient with short bowel syndrome (SBS) in which the colon is connected to the remaining small intestine, or a patient expected to have SBS in which the colon is connected to the remaining small intestine after surgery, e.g., intestinal resection. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to enhance intestinal absorption by the patient is used. h(Gly2)GLP-2 is administered intravenously at a daily dose of 0.04-0.06 mg / kg body weight, e.g., 0.05 mg / kg body weight. The GLP-2 peptibody is administered by subcutaneous injection into the patient's abdomen, thigh, or arm at a dose of 30-150 μg / kg. Daily administration is possible. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2 to 16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4.

[0113] In one aspect, methods are provided for treating a patient who is dependent on parenteral nutrition and has short bowel syndrome (SBS) in which the colon is connected to the remaining small intestine, or who is expected to have SBS in which the colon is connected to the remaining small intestine after surgery, e.g., intestinal resection. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to enhance intestinal absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient who is dependent on parenteral nutrition and has a colon connected to the remaining small intestine, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient who is dependent on parenteral nutrition and has a colon connected to the remaining small intestine. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0114] In one aspect, a method is provided for increasing villus height in a patient with short bowel syndrome or predicted to have short bowel syndrome after surgery, e.g., intestinal resection, who has reduced villus height compared to a healthy individual, who receives a certain amount of weekly parenteral nutrition, and who has a colon connected to the remaining small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period after surgery. A dosing regimen effective to increase villus height in the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for treating short bowel syndrome in a patient receiving a weekly amount of parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient receiving a weekly amount of parenteral nutrition. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0115] In various embodiments and aspects described herein, the effect of h(Gly2)GLP-2 and GLP-2 peptides on stimulating the growth of the small intestinal mucosa can help reduce the amount of total parenteral nutrition (TPN) required immediately after surgery. Similar to GLP-2, h(Gly2)GLP-2 and GLP-2 peptibodies can increase the height of the villus, the depth of the intestinal crypts, and the total surface area of ​​the intestinal mucosa. The longer half-life of h(Gly2)GLP-2 and GLP-2 peptibodies compared to GLP-2 can result in more rapid and sustained increases. Therefore, even after surgical resection of the small intestine, the increase in the total surface area may compensate for the decrease in the overall length of the small intestine.

[0116] Total parenteral nutrition (TPN) has been described by Lei et al. as blunting small intestinal villi or reducing villous height. See Lei, Q. et al., Nutrients, 2016, 8:33. Administration of h(Gly2)GLP-2 or GLP-2 peptibody may prevent villous blunting, particularly if administered to patients immediately prior to surgery, during surgery, or in the postoperative period. See, for example, Figures 1-3. Administration of GLP-2 peptibody B264, GLP-2 peptibody K274, or h(Gly2)GLP-2 increased villous height. By preventing villous blunting, absorption across the small intestine may be maximized after surgery involving removal of a portion of the small intestine followed by resection.

[0117] In one aspect, a method of treating a patient with short bowel syndrome associated with a non-malignant disease is provided, the patient receiving a weekly amount of parenteral nutrition and having a colon connected to the remaining small intestine. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is intended for use in a method of treating short bowel syndrome associated with a non-malignant disease in a patient receiving a weekly amount of parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period following surgery. In another embodiment, the GLP-2 peptibody is intended for use in the manufacture of a medicament for treating short bowel syndrome associated with non-malignant disease in patients receiving weekly parenteral nutrition. The medicament can be administered immediately before surgery, during surgery, or within a period following surgery.

[0118] In one aspect, a method of treating a patient with short bowel syndrome associated with Crohn's disease is provided. The patient receives a weekly dose of parenteral nutrition. The patient also has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but may have short bowel syndrome associated with Crohn's disease after surgery, receiving a weekly dose of parenteral nutrition and having a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome associated with Crohn's disease, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with Crohn's disease. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0119] In one aspect, a method of treating a patient with short bowel syndrome with intestinal infarction is provided. The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but may have short bowel syndrome with intestinal infarction after surgery, receiving a weekly amount of parenteral nutrition and having a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome associated with intestinal infarction, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with intestinal infarction. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0120] In one aspect, a method of treating a patient with short bowel syndrome associated with or secondary to intestinal volvulus is provided. The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient does not have short bowel syndrome and is expected to have short bowel syndrome following surgery, e.g., intestinal resection to treat the volvulus, in which the patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption by the patient relative to baseline wet weight absorption is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome associated with or secondary to volvulus, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome associated with or secondary to volvulus. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0121] In one aspect, a method of treating a patient with short bowel syndrome secondary to a congenital intestinal anomaly is provided. The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but may have short bowel syndrome secondary to a congenital intestinal anomaly following surgery, e.g., intestinal resection, where the patient is expected to receive a weekly amount of parenteral nutrition and have a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption by the patient relative to baseline wet weight absorption is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome secondary to congenital intestinal abnormalities, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome secondary to congenital intestinal abnormalities. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0122] In one aspect, a method of treating a patient with short bowel syndrome without inflammatory bowel disease is provided. The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but may have short bowel syndrome without inflammatory bowel disease after surgery, e.g., intestinal resection, where the patient is expected to receive a weekly amount of parenteral nutrition and have a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2 and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition the patient receives is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome without inflammatory bowel disease, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome without inflammatory bowel disease. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0123] In one aspect, a method is provided for treating a patient with short bowel syndrome secondary to multiple strictures due to adhesions or radiation, who is receiving a weekly dose of parenteral nutrition. Alternatively, the patient may not have short bowel syndrome, but may have short bowel syndrome secondary to multiple strictures due to adhesions or radiation following surgery, e.g., intestinal resection, and who is expected to receive a weekly dose of parenteral nutrition. The method includes administering a GLP-2 receptor agonist, e.g., h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody, to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for treating short bowel syndrome secondary to multiple strictures resulting from adhesions or radiation in a patient receiving a weekly amount of parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome secondary to multiple strictures resulting from adhesions or radiation in a patient receiving a weekly amount of parenteral nutrition. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0124] In one aspect, a method of treating a patient with short bowel syndrome secondary to ischemia is provided. The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but is expected to have short bowel syndrome secondary to ischemia following surgery, e.g., intestinal resection, where the patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. The method includes administering a GLP-2 receptor agonist, e.g., h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody, to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome secondary to ischemia in a patient receiving a weekly amount of parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome secondary to ischemia in a patient receiving a weekly amount of parenteral nutrition. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0125] Such GLP-2 receptor agonists are characterized as molecules that preferably selectively bind to and stimulate the human GLP-2 receptor, as reported in U.S. Patent No. 6,077,949 to Monroe et al., issued June 20, 2000, which is incorporated herein by reference. Briefly, GLP-2 receptor agonists have been shown to be agents that, when exposed to host cells that naturally produce or are genetically transfected with the human GLP-2 receptor, induce the production or increase in the concentration of a second messenger that binds to the receptor.

[0126] In one aspect, a method is provided for treating a patient with short bowel syndrome in which at least 25% of the colon is preserved in the remaining small intestine, and the patient receives a certain amount of parenteral nutrition weekly. Alternatively, the patient may not have short bowel syndrome, but may have short bowel syndrome in which at least 25% of the colon is preserved in the remaining small intestine after surgery, e.g., intestinal resection, and is expected to receive a certain amount of parenteral nutrition weekly. The method includes administering a GLP-2 receptor agonist, e.g., h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody, to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient receiving a weekly amount of parenteral nutrition in which at least 25% of the small intestine remains intact, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient receiving a weekly amount of parenteral nutrition in which at least 25% of the small intestine remains intact.

[0127] In another aspect, a method is provided for treating a patient with short bowel syndrome (SBS) associated with increased basal levels of endogenous GLP-2 (compared to a healthy individual). The patient receives a certain amount of parenteral nutrition weekly and has a colon connected to the remaining small intestine. Alternatively, the patient may not have SBS, but is expected to have SBS associated with increased basal levels of endogenous GLP-2 (compared to a healthy individual) following surgery, e.g., intestinal resection, receiving a certain amount of parenteral nutrition weekly and having a colon connected to the remaining small intestine. The method includes administering a GLP-2 receptor agonist, e.g., h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody, to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption by the patient relative to baseline wet weight absorption is used. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient with elevated basal endogenous GLP-2 levels (compared to a healthy individual), the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient with elevated basal endogenous GLP-2 levels (compared to a healthy individual). The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0128] In another aspect, methods are provided for treating a patient with short bowel syndrome (SBS) associated with elevated basal levels of endogenous GLP-2 (compared to healthy individuals), who is dependent on parenteral nutrition. Alternatively, the patient may not have SBS, but may have SBS associated with elevated basal levels of endogenous GLP-2 (compared to healthy individuals) following surgery, e.g., intestinal resection, and who is expected to be dependent on parenteral nutrition. The methods include administering a GLP-2 receptor agonist, e.g., h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody, to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to enhance intestinal absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient with elevated basal endogenous GLP-2 levels (compared to healthy individuals) and who is dependent on parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient with elevated basal endogenous GLP-2 levels (compared to healthy individuals) and who is dependent on parenteral nutrition. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0129] In one aspect, a method is provided for treating a patient with short bowel syndrome (SBS) with similar or increased meal-stimulated endogenous GLP-2 levels (compared to a healthy individual). The patient receives a certain amount of parenteral nutrition weekly and has a colon connected to the remaining small intestine. Alternatively, the patient may not have SBS, and after surgery, e.g., intestinal resection, is expected to have SBS with similar or increased meal-stimulated endogenous GLP-2 levels (compared to a healthy individual), receive a certain amount of parenteral nutrition weekly, and have a colon connected to the remaining small intestine. The method includes administering a GLP-2 receptor agonist, e.g., h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody, to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption by the patient relative to baseline wet weight absorption is used. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient who has similar or increased (compared to a healthy individual) endogenous meal-stimulated GLP-2 levels and who is dependent on parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient who has similar or increased (compared to a healthy individual) endogenous meal-stimulated GLP-2 levels and who is dependent on parenteral nutrition. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0130] In another aspect, a method is provided for treating a patient with short bowel syndrome (SBS) in which the colon is connected to a residual small intestine ranging from about 25 cm to about 200 cm, and who is receiving a weekly dose of parenteral nutrition. Alternatively, the patient may not have SBS, but may have SBS after surgery, e.g., intestinal resection, in which the colon is connected to a residual small intestine ranging from about 25 cm to about 200 cm, and who is expected to receive a weekly dose of parenteral nutrition. The method includes administering a GLP-2 receptor agonist to the patient immediately prior to surgery, during surgery, or within a period of time after surgery. A dosing regimen effective to increase wet weight absorption by the patient relative to baseline wet weight absorption is used. The GLP-2 agonist is selected from the group consisting of a GLP-2 peptide and a GLP-2 analog. The GLP-2 agonist can be h(Gly2)GLP-2. The GLP-2 agonist can also be a GLP-2 peptibody. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. The GLP-2 agonist may be a combination of h(Gly2)GLP-2 and a GLP-2 peptibody. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient whose colon is connected to about 25 cm to about 200 cm of remaining small intestine and who receives a certain amount of parenteral nutrition weekly, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient whose colon is connected to about 25 cm to about 200 cm of remaining small intestine and who receives a certain amount of parenteral nutrition weekly. The drug can be administered immediately before surgery, during surgery, or within a period after surgery.

[0131] In one aspect, a method of treating a patient with short bowel syndrome who has an associated colon and at least about 50 cm of remaining small intestine and who receives a weekly amount of parenteral nutrition is provided. The method comprises administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient who has at least about 50 cm of remaining small intestine and who receives a weekly amount of parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately prior to surgery, during surgery, or within a period following surgery. In another embodiment, the GLP-2 peptibody is intended for use in the manufacture of a medicament for treating short bowel syndrome in a patient having at least about 50 cm of remaining small intestine and receiving a certain amount of parenteral nutrition weekly. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0132] In another aspect, methods are provided for treating a patient with short bowel syndrome without inflammatory bowel disease. The patient receives a weekly amount of parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but rather has short bowel syndrome without inflammatory bowel disease, receives a weekly amount of parenteral nutrition, and is expected to have a colon connected to the remaining small intestine. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to increase wet weight absorption compared to baseline wet weight absorption by the patient is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for treating short bowel syndrome without inflammatory bowel disease in a patient receiving a weekly amount of parenteral nutrition, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome without inflammatory bowel disease in a patient receiving a weekly amount of parenteral nutrition. The medicament can be administered immediately before surgery, during surgery, or within a period after surgery.

[0133] In another aspect, methods are provided for treating a patient with short bowel syndrome who is dependent on parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome and is expected to become dependent on parenteral nutrition after surgery, e.g., intestinal resection, and have a colon connected to the remaining small intestine. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to reduce the patient's dependence on parenteral nutrition is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient who is dependent on parenteral nutrition and has a colon connected to the remaining small intestine, the method comprising administering the GLP-2 peptibody immediately before surgery, during surgery, or within a period of time after surgery. In another embodiment, the GLP-2 peptibody is for use in the manufacture of a medicament for treating short bowel syndrome in a patient who is dependent on parenteral nutrition and has a colon connected to the remaining small intestine. The medicament can be administered immediately before surgery, during surgery, or within a period of time after surgery.

[0134] In yet another aspect, methods are provided for treating a patient with short bowel syndrome who is dependent on parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but may be expected to have short bowel syndrome after surgery, e.g., intestinal resection, resulting in parenteral nutrition dependence and a colon connected to the remaining small intestine. The methods include administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to reduce the patient's dependence on parenteral nutrition is used. h(Gly2)GLP-2 is administered intravenously at a daily dose of 0.04-0.06 mg / kg body weight, e.g., 0.05 mg / kg body weight. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises SEQ ID NO: 4. The GLP-2 peptibody is administered daily by subcutaneous injection into the abdomen, thigh, or arm at a dose of 30-150 μg / kg.

[0135] In one aspect, a method is provided for treating an adult patient with short bowel syndrome who is dependent on parenteral nutrition and has a colon connected to the remaining small intestine. Alternatively, the patient may not have short bowel syndrome, but is expected to have short bowel syndrome after surgery, e.g., intestinal resection, resulting in parenteral nutrition dependence and a colon connected to the remaining small intestine. The method includes administering h(Gly2)GLP-2, a GLP-2 analog, and / or a GLP-2 peptibody to the patient immediately prior to surgery, during surgery, or within a period following surgery. A dosing regimen effective to reduce the patient's dependence on parenteral nutrition is used. Dose adjustments can be individualized based on achievement and maintenance of therapeutic goals. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4.

[0136] In any of the above aspects and embodiments in which h(Gly2)GLP-2 and / or GLP-2 peptibody is administered immediately prior to surgery or within a period following surgery, various dosing schedules can be used. Twice-daily administration can be beneficial. Twice-daily (every 12 hours) administration usefully delivers approximately 5-250 μg / kg per dose. Benefits may be derived from schedules involving more frequent or less frequent administration. Furthermore, follow-up administration can also be performed. Such follow-up administration can occur as part of a treatment plan for longer-term administration of h(Gly2)GLP-2, a GLP-2 analog, or a GLP-2 peptibody, or can occur before such a treatment plan is instituted. Follow-up administration usefully occurs at a regular frequency, such as weekly, biweekly, monthly, quarterly, etc. Continuous administration can be usefully achieved by providing the patient with a dose effective to maintain the benefits of enhanced intestinal absorption and increased absorptive surface area resulting from initial treatment, and by administering the drug to the patient at least once every other day to every 28 days, e.g., once every other day, two or three times a week, once a week, etc. Continuous administration or follow-up administration can be important for maintaining the medical benefits provided by GLP-2 receptor agonists. That is, as described in the Examples, improvements in intestinal absorption following treatment with, for example, teduglutide, can be lost rapidly, e.g., within four weeks, when administration is discontinued.

[0137] During surgery, h(Gly2)GLP-2, GLP-2 analogs, or GLP-2 peptibodies can be administered by infusion or any other route that delivers the drug to a target site on the serosal side of intestinal tissue, such as by depot injection. When delivered by injection, the drug may be formulated as a lyophilized powder for reconstitution by the user, and may be formulated as either a unit dose or multiple doses. For example, one teduglutide formulation is described in WO 01 / 49314, published July 12, 2001, and provides a powder for reconstitution containing teduglutide with L-histidine, mannitol, and sodium phosphate. This is usefully provided in a 3 mL glass vial for reconstitution containing 10 mg of teduglutide with 1 mL of water for injection and self-administration. Another possible formulation provides 10 mg of teduglutide in a smaller volume of aqueous medium, such as 0.5 mL of water for injection.

[0138] The patient may have short bowel syndrome associated with or secondary to Crohn's disease. The patient may have short bowel syndrome associated with or secondary to mesenteric infarction. The patient may have short bowel syndrome associated with or secondary to volvulus. The patient may have short bowel syndrome associated with or secondary to congenital intestinal anomalies. The patient may have short bowel syndrome associated with or secondary to multiple strictures due to adhesions or radiation. The patient may have short bowel syndrome associated with or secondary to ischemia. The patient may have limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals). The patient may have fewer but some detectable GLP-2-producing tissues (compared to healthy individuals). The patient may have increased basal levels of endogenous GLP-2 (compared to healthy individuals).

[0139] The patient may have short bowel syndrome without inflammatory bowel disease. In certain embodiments, the short bowel syndrome is not secondary to inflammatory bowel disease. In certain embodiments, the patient has short bowel syndrome but does not have inflammatory bowel disease.

[0140] The patient may retain at least 25% of the colon in the remaining small intestine and receive some amount of parenteral nutrition weekly. In some embodiments, the patient retains at least 30% of the colon. In some embodiments, the patient retains at least 35% of the colon. In some embodiments, the patient retains at least 40% of the colon. In some embodiments, the patient retains at least 45% of the colon. In some embodiments, the patient retains at least 50% of the colon. In some embodiments, the patient retains at least 60% of the colon. In some embodiments, the patient retains at least 70% of the colon. In some embodiments, the patient retains at least 80% of the colon. In some embodiments, the patient retains at least 90% of the colon.

[0141] The patient may have short bowel syndrome with an attached colon and a remaining small intestine ranging from about 25 cm to about 200 cm. The patient may have a small intestine length ranging from about 50 to 150 cm. The patient may have at least about 50 cm of remaining small intestine and may be receiving some amount of parenteral nutrition weekly.

[0142] The patient may have endogenous GLP-2 levels in a fed state of at least about 10% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state of at least about 15% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state of at least about 20% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state of at least about 25% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state of at least about 30% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state of at least about 35% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state of at least about 40% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state of at least about 45% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 50% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 55% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 60% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 65% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 70% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 75% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 80% (compared to a healthy individual). The patient may have endogenous GLP-2 levels in a fed state that are at least about 90% (compared to a healthy individual).

[0143] The patient may have an endogenous fed state GLP-2 level of at least 10 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 15 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 20 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 25 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 30 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 35 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 40 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 45 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 50 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 55 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 60 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 65 pmol / L. The patient may have an endogenous fed state GLP-2 level of at least 70 pmol / L.

[0144] h(Gly2)GLP-2 may be administered at a daily dose of 5 to 500 μg / kg. h(Gly2)GLP-2 may be administered at a daily dose of 30 to 150 μg / kg. h(Gly2)GLP-2 may be administered intravenously at a daily dose of 0.04 to 0.06 mg / kg body weight, for example, 0.05 mg / kg body weight.

[0145] GLP-2 peptibody: 0.02-3.0 mg / kg, 0.02-0.5 mg / kg, 0.04-0.45 mg / kg, 0.08-0.4 mg / kg, 0.10-0.35 mg / kg, 0.20-0.30 mg / kg, 0.02-0.05 mg / kg, 0.03-0.04 mg / kg, 0.05-0.10 mg / kg, 0.10-0.15 mg / kg , 0.2-0.3 mg / kg, 0.3-0.4 mg / kg, 0.4-0.5 mg / kg, 0.5-0.8 mg / kg, 0.7-1.0 mg / kg, 0.9-1.2 mg / kg, 1.0-1.5 mg / kg, 1.2-1.8 mg / kg, 1.5-2.0 mg / kg, 1.7-2.5 mg / kg, or 2.0-3.0 mg / kg daily. In some embodiments, the GLP-2 peptibody comprises the sequence of any of SEQ ID NOs: 2-16. In some embodiments, the GLP-2 peptibody comprises the sequence of SEQ ID NO: 4.

[0146] h(Gly2)GLP-2 may be administered by subcutaneous injection. Subcutaneous injection may be administered in the abdomen, thigh, or arm. Subcutaneous injection may be administered before or after surgery.

[0147] The h(Gly2)GLP-2 and / or GLP-2 peptibody may be administered to the patient at least once one month prior to surgery. The h(Gly2)GLP-2 or GLP-2 analog may be administered once just prior to surgery, such as 24 hours, 18 hours, 12 hours, 9 hours, 6 hours, 3 hours, 2 hours, or 1 hour prior to surgery. Multiple doses of h(Gly2)GLP-2 or GLP-2 analogs can be administered every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours for 1, 2, 3, 4, 5, 6, or 7 days prior to surgery. The GLP-2 peptibody can be administered once subcutaneously or intravenously prior to surgery. The GLP-2 peptibody can be administered again 3, 4, 5, 6, 7, or more days after the initial administration.

[0148] Administration may occur 24 hours after surgery, 18 hours after surgery, 12 hours after surgery, 9 hours after surgery, 6 hours after surgery, 3 hours after surgery, 2 hours after surgery, or 1 hour after surgery. After surgery, the h(Gly2)GLP-2 or GLP-2 analog can be administered approximately every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours for 1, 2, 3, 4, 5, 6, or 7 days. After surgery, the GLP-2 peptibody can be administered once in a subcutaneous or intravenous formulation. The GLP-2 peptibody can be administered again 3, 4, 5, 6, 7, or more days after the first administration.

[0149] In certain embodiments of all aspects and embodiments described herein, the patient may be an adult, human, or adult.

[0150] In some embodiments, the patient receives a weekly amount of parenteral nutrition. In some embodiments, the dosing regimen is effective to reduce the amount or frequency of parenteral nutrition administration. In some embodiments, the dosing regimen is effective to increase meal-stimulated GLP-2 secretion.

[0151] The GLP-2 peptibodies of the present invention may provide advantageous properties compared to known proteins, such as, but not limited to, at least one of increased half-life, increased activity, more specific activity, increased binding activity, increased or decreased off-rate, selection or further refinement of active subsets, reduced immunogenicity, improved quality or duration of at least one desired therapeutic effect, and reduced side effects.

[0152] Typically, suitable GLP-2 peptibodies, for example, GLP-2 peptibodies comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, have an in vivo half-life of greater than about 2 hours, greater than 3 hours, greater than 4 hours, greater than 6 hours, greater than 8 hours, greater than 10 hours, greater than 12 hours, greater than 14 hours, greater than 16 hours, greater than 18 hours, greater than 20 hours, greater than 22 hours, greater than 24 hours, greater than 26 hours, greater than 28 hours, greater than 30 hours, greater than 32 hours, greater than 34 hours, greater than 36 hours, greater than 38 hours, greater than 40 hours, greater than 42 hours, greater than 44 hours, greater than 46 hours, or greater than 48 hours. In some embodiments, the recombinant GLP-2 peptibody has an in vivo half-life of 2 to 48 hours, 2 to 44 hours, 2 to 40 hours, 3 to 36 hours, 3 to 32 hours, 3 to 28 hours, 4 to 24 hours, 4 to 20 hours, 6 to 18 hours, 6 to 15 hours, and 6 to 12 hours.

[0153] GLP-2 peptibodies or specified portions thereof, or variants thereof, can be produced by at least one cell line, mixed cell line, immortalized cell, or clonal population of immortalized and / or cultured cells. Immortalized protein-producing cells can be produced using any suitable method. Preferably, at least one GLP-2 peptibody or specified portion or variant is produced by providing a nucleic acid or vector comprising DNA derived from or having a sequence substantially similar to at least one functionally rearranged or functionally rearrangeable human immunoglobulin locus, and further comprising a peptibody structure as described herein.

[0154] GLP-2 peptibodies interact with human protein ligands with varying affinities (K D ) can bind to at least one protein ligand with high affinity. In a preferred embodiment, at least one human GLP-2 peptibody of the present invention can optionally bind to at least one protein ligand with high affinity. For example, at least one GLP-2 peptibody of the present invention can bind to at least one protein ligand with an affinity of about 10 -7 K below M D , more preferably about 0.1 to 9.9 (or any range or value therein) x 10 -7 Below, x10 -8 Below, x10 -9 Below, x10 -10 Below, x10 -11 Below, x10 -12 or less or x10 -13 K less than or equal to M, or any range or value thereof D can be combined with

[0155] The affinity or avidity of a GLP-2 peptibody for at least one protein ligand can be determined experimentally using any suitable method, such as those used to determine antibody-antigen binding affinity or avidity. (See, e.g., Kuby, Janis, Immunology, W.H. Freeman and Company: New York, NY (1992)). Affinity measurements for a particular GLP-2 peptibody-ligand interaction may differ when measured under different conditions, such as salt concentration and pH value. Thus, affinity and other ligand binding parameters (e.g., K D , K. a , K. d ) measurements are preferably made using standard solutions of GLP-2 peptibody and ligand and standard buffers, such as those described herein or known in the art.

[0156] A C-terminal lysine (K) may or may not be present. Additionally, in any of the embodiments or aspects described herein, a lysine may be added to the C-terminus. In any of the embodiments or aspects described herein, the GLP-2 peptibody is generated by processing a GLP-2 precursor polypeptide comprising a signal peptide directly linked to GLP-2, using a linker between GLP-2 and the Fc region of any of IgG1, IgG2, IgG3, and IgG4. The Fc region may be IgG1 with a LALA mutation. The GLP-2 precursor polypeptide can be represented by the following formula: Signal peptide-GLP-2[A2G]-linker-IgG1(LALA)

[0157] LALA refers to the L234A and L235A (EU index numbering) mutations in the antibody. The LALA mutation significantly reduces binding to FcγR, thereby preventing unwanted antibody effector functions from occurring in GLP-2 peptibodies. See Leabman, MK et al., "Effects of altered Fc gammaR binding on antibody pharmacokinetics in cynomolgus monkeys," mAbs 5(6):2013.

[0158] A GLP-2 peptibody may comprise GLP-2 fused to an Fc region. Improved binding between the Fc region and the FcRn receptor is contemplated to result in an extended serum half-life. Therefore, in some embodiments, a suitable Fc region comprises one or more amino acid mutations that result in improved binding to FcRn. Various mutations in Fc regions that result in improved binding to FcRn are known in the art and can be adapted to practice the present invention. In some embodiments, a suitable Fc region comprises one or more mutations at one or more positions corresponding to Thr250, Met252, Ser254, Thr256, Thr307, Glu380, Met428, His433, and / or Asn434 of human IgG1.

[0159] A GLP-2 peptibody or specified portion thereof, or variant thereof, that partially or preferably substantially provides at least one GLP-2 biological activity can provide at least one activity by binding to a GLP-2 ligand, but the activity is otherwise mediated by binding of at least one ligand, e.g., a GLP-2 receptor, to GLP-2, or by other protein-dependent or protein-mediated mechanisms. As used herein, the term "GLP-2 peptibody activity" refers to an activity that exhibits at least one GLP-2-dependent activity that is about 20-10,000% greater than that of wild-type GLP-2 peptide or GLP-2[A2G] peptide, depending on the assay, and preferably at least about 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, "GLP-2 peptibodies" refers to GLP-2 peptibodies that modulate or are capable of modulating GLP-2 activity by 9%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 700%, 800%, 900%, 1000%, 2000%, 3000%, 4000%, 5000%, 6000%, 7000%, 8000%, 9000% or more.

[0160] The ability of a GLP-2 peptibody or specified portion or variant to mediate at least one protein-dependent activity is preferably assessed by at least one suitable protein biology assay, such as those described herein and / or known in the art. The human GLP-2 peptibody or specified portion or variant of the present invention can be of any class (e.g., IgG, IgA, IgM) or isotype and can comprise at least a portion of a kappa (κ) or lambda (λ) light chain. In one embodiment, the human GLP-2 peptibody or specified portion or variant comprises at least one heavy chain CH2 and CH3 of an IgG subclass, e.g., IgG1, IgG2, IgG3, or IgG4.

[0161] At least one GLP-2 peptibody or specified portion or variant of the present invention binds to at least one ligand, subunit, fragment, portion, or any combination thereof. At least one GLP-2 peptide, variant, or derivative of at least one GLP-2 peptibody, specified portion, or variant of the present invention can optionally bind to at least one specified epitope of the ligand. The binding epitope may include any combination, from at least one amino acid sequence of at least 1-3 amino acids to the entire specified stretch of consecutive amino acids in the sequence of a protein ligand, such as the GLP-2 receptor or portion thereof.

[0162] The present invention further relates to peptibodies, ligand-binding fragments, and immunoglobulin chains whose sequences comprise amino acids substantially identical to the amino acid sequences set forth herein. Preferably, such peptibodies or ligand-binding fragments thereof bind to human GLP-2 ligands, such as receptors, with high affinity (e.g., K D about 10 -7M or less). Amino acid sequences substantially identical to the sequences described herein include sequences containing conservative amino acid substitutions, as well as amino acid deletions and / or insertions. A conservative amino acid substitution refers to the substitution of a first amino acid with a second amino acid that has similar chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) to the first amino acid. Conservative substitutions include substituting one amino acid for another within the following groups: lysine (K), arginine (R), and histidine (H); aspartic acid (D) and glutamic acid (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and T; C, S, and T.

[0163] As will be appreciated by those skilled in the art, the present invention includes at least one biologically active GLP-2 peptibody or specified portion or variant of the invention. In some embodiments, the biologically active GLP-2 peptibody or specified portion or variant has a specific activity that is at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, or 15% of the specific activity of a naturally occurring (non-synthetic), endogenous, or related known insertion or fusion protein or specified portion or variant.

[0164] Methods for preparing GLP-2 peptibodies are described in U.S. Provisional Application No. 62 / 548,601, filed August 22, 2017. Additionally, any of the modifications described in application No. 62 / 548,601 can be made to the GLP-2 peptibodies described herein.

[0165] In some embodiments, the dosing regimen is effective to increase wet weight absorption by the patient compared to baseline wet weight absorption. Such patients may have short bowel syndrome associated with or secondary to Crohn's disease. Such patients may have short bowel syndrome associated with or secondary to mesenteric infarction. Such patients may have short bowel syndrome associated with or secondary to intestinal volvulus. Such patients may have short bowel syndrome associated with or secondary to congenital intestinal anomalies. Such patients may have short bowel syndrome associated with or secondary to multiple strictures due to adhesions or radiation. Such patients may have short bowel syndrome associated with or secondary to ischemia. The patient may have limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals). The patient may have fewer but some detectable GLP-2-producing tissues (compared to healthy individuals). The patient may have increased basal endogenous GLP-2 levels (compared to healthy individuals).

[0166] In some embodiments, the dosing regimen is effective in increasing intestinal absorption by the patient. Such patients may have short bowel syndrome associated with or secondary to Crohn's disease. Such patients may have short bowel syndrome associated with or secondary to mesenteric infarction. Such patients may have short bowel syndrome associated with or secondary to intestinal volvulus. Such patients may have short bowel syndrome associated with or secondary to congenital intestinal anomalies. Such patients may have short bowel syndrome associated with or secondary to multiple strictures due to adhesions or radiation. Such patients may have short bowel syndrome associated with or secondary to ischemia. The patient may have limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals). The patient may have fewer but some detectable GLP-2-producing tissues (compared to healthy individuals). The patient may have increased basal endogenous GLP-2 levels (compared to healthy individuals).

[0167] In some embodiments, the dosing regimen is effective in reducing the patient's fecal wet weight. Such patients may have short bowel syndrome associated with or secondary to Crohn's disease. Such patients may have short bowel syndrome associated with or secondary to mesenteric infarction. Such patients may have short bowel syndrome associated with or secondary to intestinal volvulus. Such patients may have short bowel syndrome associated with or secondary to congenital intestinal anomalies. Such patients may have short bowel syndrome associated with or secondary to multiple strictures due to adhesions or radiation. Such patients may have short bowel syndrome associated with or secondary to ischemia. The patient may have limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals). The patient may have fewer but some detectable GLP-2-producing tissues (compared to healthy individuals). The patient may have increased basal endogenous GLP-2 levels (compared to healthy individuals).

[0168] In some embodiments, the dosing regimen is effective in increasing the patient's urine weight. Such patients may have short bowel syndrome associated with or secondary to Crohn's disease. Such patients may have short bowel syndrome associated with or secondary to mesenteric infarction. Such patients may have short bowel syndrome associated with or secondary to intestinal volvulus. Such patients may have short bowel syndrome associated with or secondary to congenital intestinal anomalies. Such patients may have short bowel syndrome associated with or secondary to multiple strictures due to adhesions or radiation. Such patients may have short bowel syndrome associated with or secondary to ischemia. The patient may have limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals). The patient may have fewer but some detectable GLP-2-producing tissues (compared to healthy individuals). The patient may have increased basal endogenous GLP-2 levels (compared to healthy individuals). In some embodiments, the weight of the urine is increased by at least 5% compared to the weight of the patient's urine before the administration regimen, hi some embodiments, the weight of the urine is increased by at least 10% compared to the weight of the patient's urine before the administration regimen.

[0169] In some embodiments, patients with short bowel syndrome have reduced intestinal crypt depth compared to healthy individuals, and the administration regimen is effective in increasing intestinal crypt depth in the patient. The intestinal crypt depth may be within the small intestine. See, for example, Figures 1-3. Administration of GLP-2 peptibody B264, GLP-2 peptibody K274, or h(Gly2)GLP-2 increased intestinal crypt height in the small intestine after administration.

[0170] In some embodiments, patients with short bowel syndrome have a reduced number of mitotic figures per 100 epithelial cells in their intestinal crypts compared to healthy individuals, and the dosing regimen is effective to increase the number of mitotic figures per 100 epithelial cells in their intestinal crypts.

[0171] In some embodiments, the dosing regimen involves administering h(Gly2)GLP-2 for at least 21 days, which may be at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, at least 60 days, or at least 65 days.

[0172] In some embodiments, the patient is an adult and h(Gly2)GLP-2 is administered intravenously at a daily dose of 0.04 to 0.06 mg / kg body weight, for example 0.05 mg / kg body weight.

[0173] In some embodiments, the dosing regimen is effective to restore or enhance at least a portion of the patient's ileal brake mechanism. In some embodiments, the dosing regimen is effective to reduce gastric hypersecretion in patients with short bowel syndrome. In some embodiments, the dosing regimen is effective to reduce or inhibit gastric secretion in patients with short bowel syndrome. In some embodiments, the dosing regimen is effective to reduce the rate of gastric emptying in patients with short bowel syndrome. The patient may exhibit rapid gastric emptying. In some embodiments, the dosing regimen is effective to induce small intestinal growth in patients with short bowel syndrome.

[0174] In some embodiments, the dosing regimen is effective to increase transport of proteins in patients with short bowel syndrome. Transport of proteins can be across the small intestine, for example, across the villi, across the intestinal crypts, or across both the villi and the intestinal crypts.

[0175] In some embodiments, the dosing regimen is effective in reducing the likelihood of recurrence of dehydration in patients with short bowel syndrome. In some embodiments, the dosing regimen is effective in reducing the likelihood of recurrence of renal failure in patients with short bowel syndrome. In some embodiments, the dosing regimen is effective in reducing the recurrence of kidney stones in patients with short bowel syndrome. In some embodiments, the dosing regimen is effective in increasing intestinal absorption by patients with short bowel syndrome. In some embodiments, the dosing regimen is effective in reducing the patient's dependence on parenteral nutrition.

[0176] In some embodiments, the administration regimen is effective in increasing the villus height (of the small intestine) of the patient. Villus height and intestinal crypt depth can be measured using a light microscope (ocular micrometer) as the average value of 10 appropriately oriented villi and intestinal crypts. The number of mitotic figures per 100 intestinal crypt epithelial cells can also be calculated.

[0177] In some embodiments, the dosing regimen is effective in increasing intestinal crypt height (in the small intestine) in said patient. [Example]

[0178] The following examples further explain and demonstrate the present invention. However, the use of these examples and other examples anywhere in the specification is merely illustrative and does not limit the scope and meaning of the invention or any exemplified term. Likewise, the present invention is not limited to any particular preferred embodiment described herein. On the contrary, many modifications and variations of the present invention will become apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the spirit or scope of the present invention. Therefore, the present invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which the claims are entitled.

[0179] Example 1: Histological study of villus length and intestinal crypt depth in GLP-2 peptibody B264 The pharmacological plateau was assessed for various doses of GLP-2 peptibody B264 using small intestinal weight relative to total body weight and histological examination of intestinal villi length as primary endpoints. Eleven groups of six female CD-1 mice each were generated. These groups are summarized in Table 1 below. [Table 1]

[0180] For histological examination, 4-micron paraffin sections were prepared for hematoxylin and eosin (H&E) staining and Ki67 IHC staining. After whole-slide scanning, Ki67 was analyzed by measuring the length of the villi and the depth of the intestinal crypts using an imagescope. The antibody against Ki67 was a rabbit antibody sold by Adcam® under catalog number ab616667. This antibody was used at a test concentration of 1:100 and detected using the Leica® Refine kit. The Ki67 staining results are shown in Figures 4, 5A, and 5B. GLP-2 peptibody B264, GLP-2 peptibody K274, and GLP-2[A2G] peptide were strongly localized to the villi and intestinal crypt cells. For further data and examples regarding GLP-2 peptibody B264, GLP-2 peptibody K274, and GLP-2[A2G] peptide, see, e.g., Example 13 of U.S. Provisional Application No. 62 / 548,601, filed August 22, 2017.

[0181] Example 2: Pre-operative administration of GLP-2 peptibody to patients A patient with Crohn's disease is scheduled to undergo small bowel resection surgery in 1 month. The patient is expected to have a 150 cm long small bowel after surgery. The small bowel is expected to remain connected to the large bowel. The patient is expected to develop mild short bowel syndrome and require parenteral nutrition support. As part of a treatment plan to reduce postoperative inflammation, a problem in Crohn's disease, and to minimize the need for parenteral nutrition support, the patient will be administered a GLP-2 peptibody subcutaneously weekly at a dose of approximately 1.4 mg / kg. The patient will be monitored for any side effects related to digestion and intestinal absorption.

[0182] Example 3: Pre-operative administration of teduglutide to patients A patient with Crohn's disease is scheduled to undergo small bowel resection surgery in 1 month. The patient is expected to have a 150 cm length of small bowel after surgery. The small bowel is expected to remain connected to the large bowel. The patient is expected to develop mild short bowel syndrome and require parenteral nutritional support. As part of a treatment plan to reduce postoperative inflammation, a Crohn's disease problem, and minimize the need for parenteral nutritional support, the patient will receive 0.05 mg / kg of h(Gly2)GLP-2 intravenously daily. The patient will be monitored for any side effects related to digestion and intestinal absorption.

[0183] Example 4: Intra- and Post-Surgery Administration of GLP-2 Peptibodies to Patients A patient with intestinal volvulus is undergoing small bowel resection surgery. The patient is expected to have a 100 cm length of small bowel after surgery. The small bowel is expected to remain connected to the large bowel after surgery. The patient is expected to develop short bowel syndrome and require parenteral nutrition support. As part of a treatment plan to reduce inflammation from surgery and minimize the need for parenteral nutrition support, h(Gly2)GLP-2 is administered intravenously to the patient during surgery. The daily dose administered is 0.05 mg / kg body weight. After surgery, h(Gly2)GLP-2 is administered intravenously at a daily dose of 0.05 mg / kg body weight. The patient is monitored to determine whether parenteral nutrition support can be reduced or discontinued.

[0184] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the present invention, in addition to the embodiments described herein, will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Furthermore, it should also be understood that all values ​​are approximate and are provided for illustrative purposes.

[0185] Patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entireties. Finally, preferred embodiments of the present invention are described in sections.

[0186] [Embodiment 1] A method for treating a patient undergoing surgery and having short bowel syndrome, comprising administering h(Gly2)GLP-2, a GLP-2 analog and / or a GLP-2 peptibody to the patient within 48 hours of surgery.

[0187] [Embodiment 2] 1. A method of treating a patient undergoing surgery and having short bowel syndrome, comprising administering a GLP-2 peptibody to the patient within 48 hours after surgery.

[0188] [Embodiment 3] 3. The method of embodiment 2, wherein the GLP-2 peptibody comprises one of the sequences set forth in SEQ ID NOs: 2-16.

[0189] [Embodiment 4] 3. The method of embodiment 2, wherein said GLP-2 peptibody comprises the sequence set forth in SEQ ID NO:2.

[0190] [Embodiment 5] 3. The method of embodiment 2, wherein said GLP-2 peptibody comprises the sequence set forth in SEQ ID NO:4.

[0191] [Embodiment 6] 6. The method of any of embodiments 2-5, wherein the GLP-2 peptibody is administered subcutaneously to the patient at a dose of about 1.4 mg / kg.

[0192] [Embodiment 7] 7. The method of embodiment 6, wherein the GLP-2 peptibody is administered to the patient within 12 hours after surgery.

[0193] [Embodiment 8] 8. The method according to any one of embodiments 1 to 7, wherein the patient is receiving parenteral nutrition.

[0194] [Embodiment 9] 9. The method of embodiment 8, wherein the patient receives an amount of parenteral nutrition weekly, and the method is effective to reduce the amount of parenteral nutrition the patient receives.

[0195] [Embodiment 10] 10. The method of embodiment 8 or 9, wherein the method is effective to eliminate the need for the patient to receive parenteral nutrition.

[0196] [Embodiment 11] 11. The method of any of embodiments 1 to 10, wherein the patient has short bowel syndrome secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, ischemia.

[0197] [Embodiment 12] The patient: a) Limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals); b) fewer, but some detectable, GLP-2-producing tissues (compared to healthy individuals), and c) increased basal endogenous GLP-2 levels (compared to healthy individuals) 12. The method according to any one of embodiments 1 to 11, wherein the method comprises one or more of:

[0198] [Embodiment 13] 13. The method of any of embodiments 1 to 12, wherein said method is effective to increase wet weight absorption in the intestinal tract, to enhance energy absorption in the intestinal tract, or to reduce the wet weight of feces.

[0199] [Embodiment 14] A method for treating a patient undergoing surgery and expected to develop short bowel syndrome after surgery, the method comprising administering h(Gly2)GLP-2, a GLP-2 analog and / or a GLP-2 peptibody to the patient during surgery.

[0200] [Embodiment 15] 15. The method of embodiment 14, wherein said GLP-2 peptibody is administered to said patient.

[0201] [Embodiment 16] 16. The method of embodiment 15, wherein the GLP-2 peptibody comprises one of the sequences set forth in SEQ ID NOs: 2-16.

[0202] [Embodiment 17] 16. The method of embodiment 15, wherein said GLP-2 peptibody comprises the sequence set forth in SEQ ID NO:2.

[0203] [Embodiment 18] 16. The method of embodiment 15, wherein said GLP-2 peptibody comprises the sequence set forth in SEQ ID NO:4.

[0204] [Embodiment 19] 19. The method of any of embodiments 15-18, wherein the GLP-2 peptibody is administered subcutaneously to the patient at a dose of about 1.4 mg / kg.

[0205] [Embodiment 20] 20. The method of any of embodiments 14 to 19, further comprising administering h(Gly2)GLP-2, a GLP-2 analogue and / or a GLP-2 peptibody to said patient within 48 hours after surgery.

[0206] [Embodiment 21] 21. The method according to any of embodiments 14 to 20, wherein the patient is expected to receive parenteral nutrition after surgery.

[0207] [Embodiment 22] 22. The method of embodiment 21, wherein the patient is expected to receive an amount of parenteral nutrition weekly, and the method is effective to reduce the amount of parenteral nutrition the patient receives.

[0208] [Embodiment 23] 23. The method of embodiment 21 or 22, wherein the method is effective to eliminate the need for the patient to receive parenteral nutrition.

[0209] [Embodiment 24] 24. The method of any of embodiments 14 to 23, wherein the patient has short bowel syndrome secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, ischemia.

[0210] [Embodiment 25] The patient: a) Limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals); b) fewer, but some detectable, GLP-2-producing tissues (compared to healthy individuals), and c) increased basal endogenous GLP-2 levels (compared to healthy individuals) 25. The method of any one of embodiments 14 to 24, comprising one or more of:

[0211] [Embodiment 26] 26. The method of any of embodiments 14 to 25, wherein the method is effective to increase wet weight absorption in the intestinal tract, to enhance energy absorption in the intestinal tract, or to reduce the wet weight of feces.

[0212] [Embodiment 27] A method for treating a patient who is expected to develop short bowel syndrome after surgery, the method comprising administering h(Gly2)GLP-2, a GLP-2 analog and / or a GLP-2 peptibody to the patient before surgery.

[0213] [Embodiment 28] The method of embodiment 27, wherein the h(Gly2)GLP-2 and / or GLP-2 peptibody is administered to the patient at least once within one month prior to surgery.

[0214] [Embodiment 29] 30. The method of embodiment 27 or 28, wherein the GLP-2 peptibody is administered to the patient.

[0215] [Embodiment 30] 30. The method of embodiment 29, wherein the GLP-2 peptibody comprises one of the sequences set forth in SEQ ID NOs: 2-16.

[0216] [Embodiment 31] 30. The method of embodiment 29, wherein the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO:2.

[0217] [Embodiment 32] 30. The method of embodiment 29, wherein the GLP-2 peptibody comprises the sequence set forth in SEQ ID NO:4.

[0218] [Embodiment 33] 33. The method of any of embodiments 29-32, wherein the GLP-2 peptibody is administered subcutaneously to the patient at a dose of about 1.4 mg / kg.

[0219] [Embodiment 34] 34. The method according to any one of embodiments 27 to 33, wherein the patient is expected to receive parenteral nutrition after surgery.

[0220] [Embodiment 35] 35. The method of embodiment 34, wherein the patient is expected to receive an amount of parenteral nutrition weekly, and the method is effective to reduce the amount of parenteral nutrition the patient receives.

[0221] [Embodiment 36] 36. The method of embodiment 34 or 35, wherein the method is effective to eliminate the need for the patient to receive parenteral nutrition.

[0222] [Embodiment 37] 37. The method of any of embodiments 27 to 36, wherein the patient is expected to develop short bowel syndrome after surgery secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, and ischemia.

[0223] [Embodiment 38] If the patient undergoes surgery, a) Limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals); b) fewer, but some detectable, GLP-2-producing tissues (compared to healthy individuals), and c) increased basal endogenous GLP-2 levels (compared to healthy individuals) 37. The method of any one of embodiments 27 to 36, which is expected to result in one or more of:

[0224] [Embodiment 39] 39. The method of any of embodiments 27 to 38, wherein the method is effective to increase wet weight absorption in the intestinal tract, to enhance energy absorption in the intestinal tract, or to reduce the wet weight of feces.

Claims

1. 1. A composition for treating a patient undergoing surgery who is expected to develop short bowel syndrome after surgery, the composition comprising h(Gly2)GLP-2, the composition being administered to the patient during surgery.

2. 10. The composition of claim 1, further administered to the patient within 48 hours after surgery.

3. 3. The composition of claim 1 or 2, wherein the patient is expected to receive parenteral nutrition after surgery.

4. 4. The composition of claim 3, wherein the patient is expected to receive a certain amount of parenteral nutrition each week, and the composition is effective to reduce the amount of parenteral nutrition the patient receives.

5. 5. The composition of claim 3 or 4, which is effective in eliminating the need for the patient to receive parenteral nutrition.

6. 6. The composition of any one of claims 1 to 5, wherein the patient has short bowel syndrome secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, and ischemia.

7. The patient: a) limited but some detectable meal-stimulated GLP-2 secretion compared to healthy individuals; b) less but some detectable GLP-2 producing tissues compared to healthy individuals, and c) increased basal levels of endogenous GLP-2 compared to healthy individuals The composition according to any one of claims 1 to 6, comprising one or more of:

8. 8. The composition of any one of claims 1 to 7, which is effective in increasing intestinal wet weight absorption, enhancing intestinal energy absorption, or reducing fecal wet weight.

9. The composition of any one of claims 1 to 8, wherein the composition is administered to the patient subcutaneously or intravenously.

10. A composition for treating a patient who is expected to develop short bowel syndrome after surgery, the composition comprising h(Gly2)GLP-2, and administered to the patient before surgery.

11. 11. The composition of claim 10, wherein the composition is administered to the patient at least once within one month prior to surgery.

12. 12. The composition of claim 10 or 11, wherein the patient is expected to receive parenteral nutrition after surgery.

13. 13. The composition of claim 12, wherein the patient is expected to receive a certain amount of parenteral nutrition each week, and the composition is effective to reduce the amount of parenteral nutrition the patient receives.

14. 14. The composition of claim 12 or 13, which is effective in eliminating the need for the patient to receive parenteral nutrition.

15. 15. The composition of any one of claims 10 to 14, wherein after surgery the patient is expected to develop short bowel syndrome secondary to one or more of Crohn's disease, intestinal infarction, intestinal volvulus, multiple strictures due to adhesions or radiation, and ischemia.

16. After surgery, the patient: a) limited but some detectable meal-stimulated GLP-2 secretion (compared to healthy individuals); b) fewer, but some detectable, GLP-2-producing tissues (compared to healthy individuals); and c) increased basal endogenous GLP-2 levels (compared to healthy individuals); The composition according to any one of claims 10 to 15, which is expected to produce one or more of the following:

17. 17. The composition of any one of claims 10 to 16, which is effective to increase intestinal wet weight absorption, enhance intestinal energy absorption, or reduce fecal wet weight.

18. The composition of any one of claims 10 to 17, wherein the composition is administered to the patient subcutaneously or intravenously.

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