PHASE I TRIAL OF MURINE ANTI-GANGLIOSIDE (GD2) MONOCLONAL ANTIBODY (Mab) 14G2A IN CANCER PATIENTS

Murray, James L.; Cunningham, James; Brewer, Hannah; Janus, M; Podoloff, Donald A.; kamakar, V. P. Bhad; Kasi, Leela P.; Shah, Rutvi; Benjamin, Robert S.; Legha, Sewa S.; Plager, Carl; Papadopoulos, N; Jaffee, N.; Ater, J; Mujoo, Kalpana; Itoh, Kyogo; Ross, Malcolm S.; Bucana, Corazon D.; Rosenblum, M. G.

doi:10.1097/00002371-199202000-00041

Cited by 3 publications

(6 citation statements)

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“…While the mean t~/2 of 2.8 + 2.8 h is comparable to the e~ half-lives reported by Handgretinger et al and Murray et al, our mean t~/a was shorter than that reported by the latter two investigators [16,32]. Different methodologies used for the measurement of 14G2a serum levels may in part account for the discrepancy.…”

Section: Discussionsupporting

confidence: 62%

“…These data not only indicate that labeled and unlabeled mAb may have different elimination halflives with a longer t~/2 for unlabeled mAb, but also hint at altered distribution and clearance kinetics of both. Overall, unlabeled mAb 14G2a displays two-compartment whole-body clearance as observed in three out of four phase I trials using this same murine anti-GD2 mAb [16,32,37]; however, labeled mAb 14G2a had one-compartment clearance [21,32,35].…”

Section: Discussionmentioning

confidence: 99%

“…In a study of anti-GD2 mAb 14G2a Handgretinger et al reported pharmacokinetic data from 3/9 patients treated, with ~ half-lives ranging from 0.66 h to 1.98 h and )3 half-lives from 30.13 h to 53.33 h [16]. In another phase I trial of mAb 14G2a, with a very heterogeneous group of patients, including 6 pediatric patients with neuroblastoma and 17 adult patients, Murray et al observed a wide wLriation of elimination half-lives ranging from 7 h to 162 h [32]. All patients presented with a variety of GD2-positive malignancies [-32].…”

Section: Discussionmentioning

confidence: 99%

“…So far, two phase I studies of 14G2a in adults with GD2-positive tumors have been conducted [32,35]. Pharmacokinetics of mAb 14G2a were reported for both trials and in neither trial was mAb elimination dose-dependent [21,32,35] [32] respectively. Moreover, the pharmacokinetics of 1311-14G2a indicated one-compartment clearance in both trials.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the pharmacokinetics of 1311-14G2a indicated one-compartment clearance in both trials. Interestingly, Murray et al, upon analysis of the serum kinetics of unlabeled mAb 14G2a, reported a mean "terminal half-life" of 62 • 20 h with a range of 7-164 h [32]. These data not only indicate that labeled and unlabeled mAb may have different elimination halflives with a longer t~/2 for unlabeled mAb, but also hint at altered distribution and clearance kinetics of both.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients

Uttenreuther-Fischer

Huang

Reisfeld

et al. 1995

Cancer Immunol Immunother

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A phase I trial of a murine anti-ganglioside (GD2) monoclonal antibody (mAb) 14G2a was conducted in 14 neuroblastoma patients and 1 osteosarcoma patient to assess its safety, toxicity and pharmacokinetics in pediatric patients. The pharmacokinetics of mAb 14G2a were biphasic with a t alpha 1/2 of 2.8 +/- 2.8 h and a t beta 1/2 of 18.3 +/- 11.8 h. In general, t beta 1/2 was dose-dependent with a level of significance of P = 0.036, and it reached a plateau at doses of 250 mg/m2 or more. Overall the peak serum levels were dose-dependent at P < 0.001. However, they demonstrated an abrupt increase between doses of 100 mg/m2 and 250 mg/m2. The latter two suggest a saturable mechanism for mAb elimination. In addition, peak serum concentrations were observed earlier at higher mAb doses, which indicates the achievement of a steady state. The t beta 1/2 of mAb 14G2a in children appears to be shorter than in adults. Furthermore, 2 patients demonstrated a considerable decrease in t beta 1/2 following retreatment with 14G2a. This was paralleled by high human anti-(mouse Ig) antibody levels. This study represents the first comprehensive analysis of murine mAb pharmacokinetics in children and will be useful in the future design of mAb therapy.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients

Uttenreuther-Fischer

Huang

Reisfeld

et al. 1995

Cancer Immunol Immunother

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Emerging Therapeutic Concepts IV: Anti‐idiotypic Antibodies

Fischer¹,

Uttenreuther-Fischer²

2007

Handbook of Therapeutic Antibodies

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Molecular Characterization of the Anti-Idiotypic Immune Response of a Relapse-Free Neuroblastoma Patient following Antibody Therapy: A Possible Vaccine against Tumors of Neuroectodermal Origin?

Uttenreuther-Fischer

Krüger

Fischer

2006

The Journal of Immunology

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Neuroblastoma treatment with chimeric antidisialoganglioside GD2 Ab ch14.18 showed objective antitumor responses. Production of anti-idiotypic Abs (Ab2) against ch14.18 (Ab1) in some cases was positively correlated with a more favorable prognosis. According to Jerne’s network theory, a subset of anti-idiotypic Abs (Ab2β) carries an “internal image” of the Ag and induces Abs (Ab3) against the original Ag. The molecular origin of an anti-idiotypic Ab response in tumor patients was not investigated previously. To clone anti-idiotypic Abs, B cells of a ch14.18-treated neuroblastoma patient with Ab2 serum reactivity were used to construct Ab phage display libraries. After repeated biopannings on ch14.18 and its murine relative, anti-GD2 mAb 14G2a, we selected 40 highly specific clones. Sequence analysis revealed at least 10 of 40 clones with different Ig genes. Identities to putative germline genes ranged between 94.90 and 100% for VH and between 93.90 and 99.60% for VL. An overall high rate of replacement mutations suggested a strong Ag-driven maturation of the anti-idiotypic Abs. Two clones that were analyzed further, GK2 and GK8, inhibited binding of ch14.18 to GD2 just as the patient’s serum did. GK8 alone inhibited >80% of the patient’s anti-idiotypic serum Abs in binding to ch14.18. Rabbits vaccinated with GK8 or GK2 (weaker) produced Ab3 against the original target Ag GD2. GK8 may be useful as a tumor vaccine for CD3-positive tumors.

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PHASE I TRIAL OF MURINE ANTI-GANGLIOSIDE (GD2) MONOCLONAL ANTIBODY (Mab) 14G2A IN CANCER PATIENTS

Cited by 3 publications

References 0 publications

Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients

Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients

Emerging Therapeutic Concepts IV: Anti‐idiotypic Antibodies

Molecular Characterization of the Anti-Idiotypic Immune Response of a Relapse-Free Neuroblastoma Patient following Antibody Therapy: A Possible Vaccine against Tumors of Neuroectodermal Origin?

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