An evaluation of antibodies and clinical resistance to salmon calcitonin

“…Therefore, aggregation constitutes a serious problem that leads to a significant decrease in the hormone activity (12). Moreover, aggregation stimulates undesirable immune responses, resulting in resistance or allergic reactions in patients (13,14), and drug-induced cytotoxicity (15). On the contrary, sCT shows a higher potency combined with a longer in vivo half-life when compared with hCT and a substantially lower propensity to aggregate (7, 11), but it has been shown to develop side effects such as anorexia and vomiting (16,17).…”

mentioning

confidence: 99%

Converting the Highly Amyloidogenic Human Calcitonin into a Powerful Fibril Inhibitor by Three-dimensional Structure Homology with a Non-amyloidogenic Analogue

Andreotti

Vitale

Avidan-Shpalter

et al. 2011

Journal of Biological Chemistry

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Irreversible aggregation limits bioavailability and therapeutic activity of protein-based drugs. Here we show that an aggregation-resistant mutant can be engineered by structural homology with a non-amyloidogenic analogue and that the aggregation-resistant variant may act as an inhibitor. This strategy has successfully been applied to the amyloidogenic human calcitonin (hCT). Including only five residues from the non-amyloidogenic salmon calcitonin (sCT), we obtained a variant, polar human calcitonin (phCT), whose solution structure was shown by CD, NMR, and calculations to be practically identical to that of sCT. phCT was also observed to be a potent amyloidogenesis inhibitor of hCT when mixed with it in a 1:1 ratio. Fibrillation studies of phCT and the phCT-hCT mixture mimicked the sCT behavior in the kinetics and shapes of the fibrils with a dramatic reduction with respect to hCT. Finally, the effect of phCT alone and of the mixture on the intracellular cAMP level in T47D cells confirmed for the mutant and the mixture their calcitonin-like activity, exhibiting stimulation effects identical to those of sCT, the current therapeutic form. The strategy followed appears to be suitable to develop new forms of hCT with a striking reduction of aggregation and improved activity. Finally, the inhibitory properties of the aggregation-resistant analogue, if confirmed for other amyloidogenic peptides, may favor a new strategy for controlling fibril formation in a variety of human diseases.The intrinsic propensity of peptides and proteins to irreversibly aggregate limits the development of protein-based drugs because aggregation compromises their bioavailability and therapeutic activity and increases the risk of immunogenic reactions (1, 2). Possible strategies for overcoming these problems involve the design of specific analogues in which the physicochemical properties of the molecule are changed through mutations of a small number of amino acids (3) or the development of safe inhibitors such as small peptide fragments (4 -6). However, because at the moment large molar excesses of inhibitors are used, their pharmacological efficacy appears to be of limited relevance.A good example of a bioactive peptide with limited pharmaceutical potential due to a high tendency to aggregate is human calcitonin (hCT).3 It is a 32-residue hormone synthesized and secreted by the C cells of the thyroid and involved in calcium regulation and bone dynamics (7). In its common form it presents an N-terminal disulfide bridge between positions 1 and 7 and a C-terminal proline amide residue. Only eight residues are common to all species so far studied, and these are clustered at the two ends of the molecule. The salmon variant (sCT) is widely used in the treatment of osteoporosis and Paget disease as well as malignancy-caused hypercalcemia and musculoskeletal pain (8,9). This is because hCT shows an extremely high tendency to form amyloid fibrils both in vivo in patients with medullar carcinoma of the thyroid (10) and in vitro in preparations desi...

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“…Several investigators have reported their observations employing calcitonin in Paget's disease of bone, as well as other skeletal disorders (1)(2)(3)(4)(5). The failure to observe suppression of skeletal turnover to normal levels in Paget's disease during calcitonin therapy has been thought to indicate secondary hyperparathyroidism (16, 17), even though antibody formation to PCT and SCT has been reported (17,18). Others have not detected antibodies but have observed elevations of serum alkaline phosphatase during continued PCT therapy (5).…”

Section: Discussionmentioning

confidence: 99%

Calcitonin Resistance: Clinical and Immunologic Studies in Subjects with Paget's Disease of Bone Treated with Porcine and Salmon Calcitonins

Haddad¹,

Caldwell²

1972

J. Clin. Invest.

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An evaluation of antibodies and clinical resistance to salmon calcitonin

Cited by 134 publications

References 19 publications

Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial.

Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial.

Converting the Highly Amyloidogenic Human Calcitonin into a Powerful Fibril Inhibitor by Three-dimensional Structure Homology with a Non-amyloidogenic Analogue

Calcitonin Resistance: Clinical and Immunologic Studies in Subjects with Paget's Disease of Bone Treated with Porcine and Salmon Calcitonins

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