Development of a Humanized Monoclonal Antibody (MEDI‐493) with Potent In Vitro and In Vivo Activity against Respiratory Syncytial Virus

Johnson, Syd; Oliver, Cynthia N.; Prince, Gregory A.; Hemming, Val G.; Pfarr, David S.; Wang, Sheau-Chiann; Dormitzer, Melissa; O'grady, J. E.; Koenig, Scott; Tamura, James; Woods, R. Claude; Bansal, Gulshan; Couchenour, Debra A.; Tsao, Eric; Hall, William C.; Young, James F.

doi:10.1086/514115

Cited by 587 publications

(436 citation statements)

References 51 publications

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“…2A). Variants 19,21,22,24, and 25 consistently exhibited a moderate, although significant enhancement in CDC activity on various cell types tested (Fig. 3, C and D) when compared with their wild-type counterpart (12G3H11).…”

Section: Cdc Activitymentioning

confidence: 91%

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Modulation of the Effector Functions of a Human IgG1 through Engineering of Its Hinge Region

Dall’Acqua¹,

Cook²,

Damschroder³

et al. 2006

The Journal of Immunology

126

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We report here the engineering of a humanized anti-human EphA2 mAb (mAb 12G3H11) in an effort to explore the relationship between the hinge of a human IgG1 and its effector functions. mAb 12G3H11, used here as a model, is directed against the human receptor tyrosine kinase EphA2, which is an actively investigated target for cancer therapy due to its up-regulation in many cancer cells. Various rational modifications were introduced into the hinge region of mAb 12G3H11. These mutations were predicted to modulate the hinge’s length, flexibility, and/or biochemical properties. We show that the upper and middle hinge both play important, although functionally distinct roles. In particular, middle hinge modifications predicted to decrease its rigidity or length as well as eliminating either one of its two cysteine residues had a strong negative impact on C1q binding and complement-dependent cytotoxicity. Disruption of covalent bonds between both H chains may account in part for these effects. We also describe middle hinge mutants with a significantly decreased ability to bind FcγRIIIA and trigger Ab-dependent cell-mediated cytotoxicity. Conversely, we also generated upper hinge mutants exhibiting an increase in C1q binding and complement-dependent cytotoxicity activity. Therefore, this approach represents a novel strategy to fine-tune the biological activity of a given human IgG1. We also define, for the first time in such a systematic fashion, the relationship between various characteristics of the middle and upper hinge and the corresponding effector functions.

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Section: Cdc Activitymentioning

confidence: 91%

“…The variable light and variable heavy genes of mAb 12G3H11 were individually cloned into mammalian expression vectors encoding a human CMV major immediate early enhancer, promoter, and 5Ј-untranslated region (20). In this system, a human ␥1 chain is secreted along with a human chain (21).…”

Section: General Description Of the Test Ab And Expression Vectorsmentioning

confidence: 99%

Modulation of the Effector Functions of a Human IgG1 through Engineering of Its Hinge Region

Dall’Acqua¹,

Cook²,

Damschroder³

et al. 2006

The Journal of Immunology

126

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“…Indeed, some practice guidelines have suggested that ribavirin has comparatively better efficacy in the immunosuppressed population. 27 A humanized monoclonal antibody to the F protein of RSV (MEDI-493, palivizumab, Synagis) 28 became available after this protocol closed, and has a similar RSV preventative effect as RSV-IGIV for its indicated use. 29 This monoclonal antibody has also been shown to have an antiviral treatment effect in immunocompetent infants: RSV concentrations in palivizumab-treated patients dropped by 1.7 log at 24 h and 2.5 log at 48 h after a single intravenous 15 mg/kg dose, as compared to a 0.6 log (P = 0.004) and a 1.0 log (P = 0.012) drop in the placebo group at the same time points.…”

Section: Tablementioning

confidence: 99%

Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation – a compassionate use experience

DeVincenzo

Hirsch²,

Fuentes³

et al. 2000

Bone Marrow Transplant

112

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Summary:Respiratory syncytial virus (RSV) pneumonia in BMT recipients carries a mortality rate of approximately 50-70% despite ribavirin (Virazole) treatment. In both immunocompetent and immunocompromised animal models, RSV neutralizing antibodies rapidly reduce pulmonary virus load after a single dose. RSV-IGIV (RespiGam) is an IgG immune globulin with high concentrations of RSV neutralizing antibody (Ͼ19 200 MU/ml). From June 1991 to February 1996, a compassionate-use protocol using RSV-IGIV for treatment of RSV infections was conducted. Eleven children at multiple centers, mean age 3.3 years (4 months to 9 years), were undergoing BMT and met the protocol criteria. They received a single 1500 mg/kg dose of RSV-IGIV infused over 12 h at a median of 5 days (1-37 days) after RSV symptom onset. Ten of these patients received prior or concurrent aerosolized ribavirin. Serum RSV neutralizing titers were measured in five patients and showed a 3-to 30-fold increase 24 h after RSV-IGIV infusion. Adverse events were mild. One of 11 (9.1%) patients died from their RSV illness (91% RSV survival). In comparison to previously published reports, RSV-IGIV treatment of RSV pneumonia in BMT patients may increase survival above that in such patients treated with ribavirin alone. Bone Marrow Transplantation (2000) 25, 161-165. Keywords: respiratory syncytial virus; bone marrow transplantation; immune globulin; treatment; ribavirin; palivizumab Respiratory syncytial virus (RSV) is a well recognized and often fatal complication of bone marrow transplantation. Upper or lower respiratory tract infection (URTI/LRTI) with RSV has been reported to occur in 7% to 20% of hospitalized BMT patients, primarily during the 6-month winter season (November to May). 1-3 Many of these RSV infected patients develop pneumonia and face a high risk of mortality. [1][2][3] The reported mortality rate in BMT patients who develop RSV-LRTI approaches 100% for those not treated with antivirals and 50% to 70% for those promptly treated with ribavirin (Virazole). [3][4][5][6][7][8][9][10][11][12][13] From the literature, it appears that there are no survivors among RSV-LRTI transplant patients who progress to mechanical ventilation before antiviral therapy has been initiated. 2,12 Although RSV pneumonia occurring more than 100 days post-BMT has been associated with lower mortality rates, 12,13 the mortality rate of RSV pneumonia does not differ before and after engraftment during the early post-transplant period. 3,14 Aerosolized ribavirin is the only Federal Drug Administration (FDA) approved drug for treatment of established RSV disease, 15 but its efficacy in BMT patients with RSV pneumonia is considered poor. The beneficial effects of immune globulin therapy on established RSV disease have been clearly demonstrated in experimental animals. In both immunocompetent and immunocompromised animal models of RSV infection, IgG immune globulin preparations have been shown to rapidly reduce the pulmonary virus load after a single large parenteral dose. [16][17][1...

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“…17,18 Recently, the RSV F nanoparticles produced in insect cells were reported to be safe in healthy individuals and young women of childbearing age in phase I and II clinical trials. 19,20 Protection was reported without causing RSV disease by immunization of mice with mixed F VLP and G VLP (FG VLP) vaccines with DNA plasmids expressing F proteins as evidenced by clearing lung viral loads and preventing pulmonary inflammation.…”

Section: Discussionmentioning

confidence: 99%

Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats

Hwang

Kim

Lee

et al. 2017

Human Vaccines & Immunotherapeutics

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Vaccine-enhanced disease has been a major obstacle in developing a safe vaccine against respiratory syncytial virus (RSV). This study demonstrates the immunogenicity, efficacy, and safety of virus-like particle (VLP) vaccines containing RSV F (F VLP), G (G VLP), or F and G proteins (FG VLP) in cotton rats. RSV specific antibodies were effectively induced by vaccination of cotton rats with F VLP or FG VLP vaccines. After challenge, lung RSV clearance was observed with RSV F, G, FG VLP, and formalin inactivated RSV (FI-RSV) vaccines. Upon RSV infection, cotton rats with RSV VLP vaccines were protected against airway hyperresponsiveness and weight loss, which are different from FI-RSV vaccination exhibiting vaccine-enhanced disease of airway obstruction, weight loss, and severe histopathology with eosinophilia and mucus production. FG VLP and F VLP vaccines did not cause pulmonary inflammation whereas G VLP induced moderate lung inflammation with eosinophilia and mucus production. In particular, F VLP and FG VLP vaccines were found to be effective in inducing antibody secreting cell responses in bone marrow and lymphoid organs as well as avoiding the induction of T helper type 2 cytokines. These results provide further evidence to develop a safe RSV vaccine based on VLP platforms.

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Development of a Humanized Monoclonal Antibody (MEDI‐493) with Potent In Vitro and In Vivo Activity against Respiratory Syncytial Virus

Cited by 587 publications

References 51 publications

Modulation of the Effector Functions of a Human IgG1 through Engineering of Its Hinge Region

Modulation of the Effector Functions of a Human IgG1 through Engineering of Its Hinge Region

Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation – a compassionate use experience

Virus-like particle vaccines containing F or F and G proteins confer protection against respiratory syncytial virus without pulmonary inflammation in cotton rats

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