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(12) Patent Application Publication (10) Pub. No.: US 2003/0219843 A1 Welsch Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0219843 A1 Welsch Et Al US 200302198.43A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0219843 A1 Welsch et al. (43) Pub. Date: Nov. 27, 2003 (54) METHODS OF DIAGNOSING AND Related U.S. Application Data TREATING ABNORMAL GROWTH (60) Provisional application No. 60/343,281, filed on Dec. 20, 2001. (76) Inventors: Dean J. Welsch, St. Peters, MO (US); Kevin L. Duffin, Manchester, MO Publication Classification (US); Olga V. Nemirovskiy, St. Louis, MO (US); Dawn R. Dufield, O’Fallon, (51) Int. Cl." ....................... G01N 33/53; G01N 33/537; MO (US); Teresa Sunyer, Wildwood, G01N 33/543; CO7K 16/18 MO (US); Carol P. Howard, Fenton, (52) U.S. Cl. ..................................... 435/7.92; 530/388.25 MO (US); Mark Abrams, St. Louis, MO (US) (57) ABSTRACT A method of determining the concentration of peptides in a Correspondence Address: biological fluid resulting from the proteolytic degradation of Pharmacia Corporation extracellular matrix proteins for diagnosing growth disor Corporate Patent Department ders in vertebrates. The method includes determining the P.O. BOX 1027 concentration of peptides resulting from the proteolytic Chesterfield, MO 63006 (US) degradation of extracellular matrix proteins in a biological fluid for determining the efficacy of drugs or agents used to (21) Appl. No.: 10/326,508 treat growth disorders. A kit for determining the concentra tion of peptides resulting from the proteolytic degradation of (22) Filed: Dec. 20, 2002 extracellular matrix proteins is also disclosed. Patent Application Publication Nov. 27, 2003 Sheet 1 of 9 US 2003/0219843 A1 0. 8 0.0.0. 264. O Patent Application Publication Nov. 27, 2003. Sheet 3 of 9 US 2003/0219843 A1 suunyougun?u?ap?doaIIadKLue3eIOOJotunnoºdsSW/SVN pò?p?ÁH?ORVOS?OGGÐ?ÁHRÐXH?ddÐV??ÒT Patent Application Publication Nov. 27, 2003 Sheet 6 of 9 US 2003/0219843 A1 (899/v16)ap?dea1951eLipue(895/8*6) ap?da.ð1931eL / sdo "Aisuou sdo 'ÁSueu Patent Application Publication Nov. 27, 2003 Sheet 7 of 9 US 2003/0219843 A1 ºu?InIeuluoNuetunH Qu?InVOubuInH. 9Inã?SI/8 sdo "Aisuou sdo “Kisuau sdo 'Asuou Patent Application Publication Nov. 27, 2003 Sheet 8 of 9 US 2003/0219843 A1 6Q?n?l? +IJOJ£'ŒI9Z/uu‘DÒ?O?LO ap?deaprepue?So?9??uÁSI9dKLU93æIIOOJOUunumo3dSSW/SW Zjuu09909909709909Z09||0$0 US 2003/0219843 A1 Nov. 27, 2003 METHODS OF DAGNOSING AND TREATING normal height, weight, or developmental Stage is of dubious ABNORMAL GROWTH certainty. There is therefore a need in the art for an earlier diagnosis of growth disorders, So that a Subject may receive FIELD OF THE INVENTION therapy at an earlier Stage, preferably before overt morpho logical anomalies are present. 0001. The invention relates generally to methods for identifying and quantifying peptides and, more particularly, 0007 Treatment for a given growth disorder typically to a method for identifying and quantifying degradation involves the administration of at least one growth modulat peptides resulting from enzyme cleavage of collagen. The ing drug or agent. A Significant problem with treatment is invention also relates to the Specific peptides that result from finding an optimal dosage of growth modulating drug or enzymatic cleavage of collagen types I, II, and III in humans agent. While there are generally accepted ranges of drug and animals and the recognition of these peptides as markers dosages, a clinician will typically administer a growth in biological Samples of the activity of proteolytic enzymes modulating drug or agent in a relatively haphazard manner, in diseases or physiological conditions characterized by prescribing an arbitrary dosage of Such drug or agent and enzymatic degradation of collagen, Such as disorders involv making adjustments based upon Somatic measurements rep ing abnormal growth and development, and the identifica resenting the perceived efficacy of the drug or agent at a tion and quantification of the peptides to assess the efficacy given dosage. This method of dosing is potentially delete of growth regulating agents and drugs used to treat or control rious in that a Sub-optimal initial dose may further decrease Such diseases or physiological conditions. the treated Subject's chances of attaining the desired ultimate (adult) height, weight or development on the one hand, while an inappropriately high doses may result in unwanted BACKGROUND OF THE INVENTION Side effects of the drug or agent. 0002 Various growth disorders affect a significant num 0008 Growth modulating drugs and agents may also be ber of infants and children worldwide each year. Growth applied to non-human animals. Bovine Somatotropin pro disorders may be broadly classified into two groups: those duced by recombinant microorganisms (rbSt), or extracted growth disorders that result in Subnormal height, weight or from pituitary gland tissue, is important commercially. It development, and those growth disorders that result in increases lactation in dairy cattle and increases Size and meat abnormally elevated growth, weight or development. production in beef cattle. It is estimated that at least 20 mg 0.003 Growth disorders may arise from a variety of per animal per day is needed to effect commercially accept causes, Such as genetic predisposition, nutrition, various able improvements in production. Dosing with b0H or bSt diseases, endocrine abnormalities, injuries, exposure to tox for enhancement of bovine growth is not typically optimized ins, and even psychological disorders. for an individual animal or even for a herd of genetically Similar animals. Therefore, a potential inefficiency in dosing 0004 Treatment is most often sought for growth disor of a herd of cows or cattle may result from utilizing a Set derS resulting in below average height. This may be in part amount of growth enhancing agent or drug. due to a cultural bias toward tall Stature, Since physical height is perceived as a desirable characteristic. Indeed, the 0009 Dogs are another mammal that may benefit from word “stature' is Synonymous with respect and preeminence growth modulating drugs or agents. In addition, dogs are in a community. Sometimes used in drug Safety and efficacy Studies during 0005. However, aberrances in growth manifested as the early Stages of clinical trials. excessive height or weight may pose significant problems to 0010 Certain breeds of dogs, particularly retrievers, are affected individuals. For example, tall Subjects have greater predisposed to a condition known as canine hip dysplasia trouble Selecting automobiles in which they can comfortably (CHD). Literally, hip dysplasia (CHD), means “badly Sit, and may complain of low ceilings and doorways. Obese formed hip”. In order to understand this complex problem it individuals may face Social Stresses. Both tall and obese is first necessary to understand the anatomy of the canine Subjects tend to be more likely to develop certain chronic hip. This ball and Socket joint consists of two basic parts disorders, Such as coronary heart disease. the acetabulum and the femur. The femur, or thigh bone, 0006 Sometimes, a growth disorder may be determined consists of the head (the ball) and the neck (the part of the or Suspected perinatally, either through ultrasound during femur that joins the long shaft of the bone to the head). The pregnancy, or at birth. Intrauterine growth retardation acetabulum forms the Socket part of the joint and it is into (IUGR) may be so discerned. Infants born Small for gesta this socket that the head of the femur rests. A poor fit tional age (SGA) are Sometimes targeted for growth hor between femoral head and acetabulum is characteristic of mone therapy, or other growth promoting drug or agent dysplastic dogs. CHD can also be diagnosed if the femoral administration. Frequently, a growth disorder is undiag neck is shortened or if there is an improper angle between nosed until an age is reached when it becomes apparent that the femoral head and the long axis of the femoral neck. the Subject is developing abnormally. Measurements of 0011 Dogs are not born with CHD. As puppies grow, Somatic growth are found to lie outside of normal param muscles and ligaments Surrounding the joint become lax, eters. Such measurements may include, for example, Supine and a poor fit between the bones produces exceSS movement length or height, weight, and head circumference. At the of the acetabulum. The separation between the bones is time of diagnosis, the Subject must undergo therapy in order called Subluxation, and in Severe cases, the head of the femur to approach a normal height, weight or developmental Stage leaves the acetabulum. The surfaces of the bones are initially appropriate for the age and Sex of the Subject's peers. completely smooth, but in CHD the bones undergo remod However, Since the growth disorder is already manifested in eling. Bone rubbing against bone causes an irritation which an abnormal appearance, the probability of achieving a results in irregular bone growth and wear on the articular US 2003/0219843 A1 Nov. 27, 2003 Surfaces. These irregular Surfaces result in Osteoarthritis described production of a monoclonal antibody directed which can cause Significant pain. AS the bone of the acetabu against this carboxy-terminal “neoepitope' (Matrix Biology lar rim is ground away, it becomes Shallower and it becomes 18:331-341 (1999)). more difficult to keep the head of the femur properly Seated. 0017 U.S. Pat. No. 6,030,792 to Otterness et al., herein 0012 CHD is a polygenic, inherited trait. It is not caused incorporated by reference in its entirety, discloses antibodies by any environmental factors, but environment can influence for detecting collagen fragments resulting from collagenase the expression of the disease. Among those influences are cleavage of type II collagen, as a method of diagnosing excessive weight gain or rapid growth. Unfortunately, the arthritis, and determining the efficacy of arthritis modulating typically available diagnosis of CHD occurs through X-rays pharmaceuticals. Poole et al., U.S.
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