Development of a Human Monoclonal Antibody against Cytomegalovirus with the Aim of a Passive Immunotherapy

Masuho, Yasuhiko; Matsumoto, Yoh-ichi; Sugano, Toru; Tomiyama, Takami; Sasaki, Satoshi; Koyama, Tamotsu

doi:10.1007/978-1-349-11894-6_12

Cited by 6 publications

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors

Sato

Yamakawa

Shizume

et al. 1993

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Malignancy-associated hypercalcemia is mainly caused by excessive production of parathyroid hormone-related protein (PTHrP) by the tumor. Using anti-PTHrP-(1-34) monoclonal murine antibody (anti-PTHrP MoAb), we studied whether repeated injection of the homologous antibody would continuously decrease the serum calcium concentration in hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors, leading to prolongation of their survival time. Daily SC injections of anti-PTHrP MoAb decreased the serum calcium concentration almost to within the normal range in nude mice bearing transplanted human PTHrP-producing tumors (T3M-1, EC-GI, PC-3, and FA-6) but not in a nude mouse bearing a transplanted parathyroid carcinoma. The antibody did not affect FA-6 tumor growth either in vitro or in vivo. Pancreatic carcinoma cells (FA-6), which caused the most severe hypercalcemia, were inoculated into 6-week-old nude mice. When severe hypercalcemia (approximately 19 mg/dl) had developed, daily SC injection of anti-PTHrP MoAb was started. Within 18 days of this time point, all untreated tumor-bearing mice (n = 10) died of hypercalcemia and cachexia, whereas all the treated mice (n = 10) showed an increase in body weight and survived for at least 25 days. Histologic examination of the treated mice revealed a marked decrease in osteoclastic bone resorption, without toxicologic findings in the kidney and liver. These results suggest that passive immunization against PTHrP can continuously ameliorate the hypercalcemia and markedly prolong the survival time of severely hypercalcemic, tumor-bearing mice. If a human monoclonal antibody against PTHrP-(1-34) could be developed, then passive immunization would be potentially one of the most effective therapies for patients with malignancy-associated hypercalcemia due to excessive production of PTHrP.

show abstract

Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors

Sato

Yamakawa

Shizume

et al. 1993

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states

Yang¹,

Corvalan²,

Wang³

et al. 1999

Journal of Leukocyte Biology

158

View full text Add to dashboard Cite

Interleukin-8 (IL-8) is a potent chemotactic cytokine implicated in the pathogenesis of a number of inflammatory disease states. Agents that block the binding of IL-8 to its receptor have been shown to block inflammation in animal models of disease. This suggests that drugs specifically targeting IL-8 may prove efficacious in treating multiple human diseases. To this end, we developed a panel of fully human anti-IL-8 monoclonal antibodies (mAbs). These human antibodies were generated from XenoMouse strains, mice created by introducing megabase-size unrearranged human immunoglobulin heavy and kappa light chain loci into a mouse genome in which the corresponding endogenous loci have been inactivated. From the panel of more than 50 mAbs, two antibodies, K4.3 and K2.2, were further characterized and evaluated for their specificity, productivity, affinity, and biological activity. Both K4.3 and K2.2 bind human IL-8 with high affinity (Kd of K4.3 = 2.1x10(10) M; Kd of K2.2 = 2.5x10(-10) M). In vitro, in addition to blocking IL-8 binding to human neutrophils, K4.3 and K2.2 blocked a number of IL-8-dependent cellular functions including neutrophil activation, up-regulation of the cell adhesion receptor CD11b/CD18, and neutrophil chemotaxis, suggesting that the fully human anti-IL-8 mAbs derived from XenoMouse strains are potent anti-inflammatory agents. This was further supported by in vivo studies in which K4.3 and K2.2 significantly inhibited IL-8-induced skin inflammation in rabbits. A pharmacokinetic study in Cynomolgus monkeys demonstrated that the alpha phase half-life is 9.4 h and the beta phase 10.9 days, typical of human mAbs in monkeys. These data support advancing a fully human anti-IL-8 mAb into clinical trials to treat inflammatory diseases.

show abstract

Different antibody response to a neutralizing epitope of human cytomegalovirus glycoprotein B among seropositive individuals

Ayata

Sugano

Murayama

et al. 1994

Journal of Medical Virology

Self Cite

View full text Add to dashboard Cite

The amino-terminal portion of human cytomegalovirus glycoprotein B (HCMV-gB) was expressed as a fusion protein to analyze the neutralizing epitope recognized by human monoclonal antibody C23 and the humoral immune response to this epitope. The linear neutralizing epitope was further localized to the peptide within 17 amino acids (position 68-84) which were conserved between two HCMV laboratory strains. Ten out of 17 HCMV-seropositive human sera contained the antibody against this epitope. Although seven sera were negative for reacting with the fusion protein, the viruses isolated from the same patients retained the epitope. The immunogenicity of the epitope and the possible application of C23 human monoclonal antibody for passive immunization against HCMV infections are discussed.

show abstract

Development of a Human Monoclonal Antibody against Cytomegalovirus with the Aim of a Passive Immunotherapy

Cited by 6 publications

References 41 publications

Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors

Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors

Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states

Different antibody response to a neutralizing epitope of human cytomegalovirus glycoprotein B among seropositive individuals

Contact Info

Product

Resources

About