Phase I Study of Safety and Pharmacokinetics of a Human Anticytomegalovirus Monoclonal Antibody in Allogeneic Bone Marrow Transplant Recipients

Drobyski, William R.; Gottlieb, Mark S.; Carrigan, Donald R.; Östberg, Lars; Grebenau, Mark D.; Schran, Horst; Magid, Paul; Ehrlich, Paul H.; Nadler, Paul I.; Ash, Robert C.

doi:10.1097/00007890-199106000-00009

Cited by 31 publications

(17 citation statements)

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“…To make a variant of HuLuc63 with decreased ADCC activity (HuLuc63-AA), a variant expression plasmid with two mutations in IgG1 CH2 domain (L234A/L235A) was used; these mutations decrease ADCC via decreased Fc g-receptor binding (29). MSL109, the control IgG1 antibody used in all experiments, is a fully human anticytomegalovirus mAb (30).…”

Section: Methodsmentioning

confidence: 99%

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

Hsi

Steinle

Balasa

et al. 2008

Clinical Cancer Research

510

537

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Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models. Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.Results: CS1mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like Tcells, and CD8+ Tcells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice. Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1with HuLuc63 for the treatment of multiple myeloma.

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Section: Methodsmentioning

confidence: 99%

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

Hsi

Steinle

Balasa

et al. 2008

Clinical Cancer Research

510

537

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“…RG7667 is a combination of two monoclonal antibodies, MCMV5322A and MCMV3068A. MCMV5322A is a human immunoglobulin antibody (IgG1) that binds a neutralizing epitope on CMV glycoprotein H (gH) and is an affinitymatured version of MSL-109 (PDL Biopharma, Inc., Incline Village, NV) (33,34). MCMV5322A Fab exhibits Ͼ10-fold higher affinity than MSL-109 to baculovirus-expressed gH/gL protein as determined by surface plasmon resonance (dissociation constant [K d ] of Ͻ10 pM versus 100 pM) (34).…”

Section: Methodsmentioning

confidence: 99%

Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults

Ishida

Burgess²,

Derby³

et al. 2015

Antimicrob Agents Chemother

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dCytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n ‫؍‬ 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n ‫؍‬ 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n ‫؍‬ 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.)

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“…The human IgG1 control antibody, MSL109, is the fully human antibody to cytomegalovirus (24). Antibodies were purified using standard Protein G or Protein A affinity purification methods.…”

Section: Methodsmentioning

confidence: 99%

Antibodies to TWEAK Receptor Inhibit Human Tumor Growth through Dual Mechanisms

Culp

Choi

Zhang

et al. 2010

Clinical Cancer Research

109

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Purpose: Targeted therapeutics have significantly changed the outcome for patients diagnosed with cancer. Still, effective therapeutic intervention does not exist for many cancers and much remains to be done. The objective of this study was to identify novel genes that potentially regulate tumor growth, to target these gene products with monoclonal antibodies, and to examine the therapeutic potential of these antibodies. Experimental Design: Using cDNA microarray analysis, we identified genes overexpressed in several solid malignancies. We generated a mouse monoclonal antibody, 19.2.1, and its humanized counterpart, PDL192, to one such target, TweakR (TWEAK receptor, Fn14, TNFRSF12A, CD266), and characterized the antitumor activities in vitro and in mouse xenograft models. Results: Both 19.2.1 (mouse IgG2a) and PDL192 (human IgG1), like TWEAK, the natural ligand of TweakR, inhibited the growth of several TweakR-expressing cancer cell lines in anchorage-dependent and anchorage-independent assays in vitro. Both antibodies showed significant antitumor activity in multiple mouse xenograft models. PDL192 and 19.2.1 also induced antibody-dependent cellular cytotoxicity (ADCC) of cancer cell lines in vitro. A chimeric version of 19.2.1 containing the mouse IgG1 Fc region (19.2.1×G1) exhibited significantly less ADCC than 19.2.1. However, 19.2.1×G1 showed differential activity in vivo, with activity equivalent to 19.2.1 in one model, but significantly less efficacy than 19.2.1 in a second model. These results indicate that PDL192 and 19.2.1 mediate their antitumor effects by signaling through TweakR, resulting in reduced tumor cell proliferation, and by ADCC. Clin Cancer Res; 16(2); 497–508

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Phase I Study of Safety and Pharmacokinetics of a Human Anticytomegalovirus Monoclonal Antibody in Allogeneic Bone Marrow Transplant Recipients

Cited by 31 publications

References 0 publications

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults

Antibodies to TWEAK Receptor Inhibit Human Tumor Growth through Dual Mechanisms

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