A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma

Handgretinger, R.; Anderson, Kelly E.; Lang, Peter; Dopfer, R.; Klingebiel, Thomas; Schrappe, Martin; Reuland, P.; Gillies, S. D.; Reisfeld, Ralph A.; Niethammer, D.

doi:10.1016/0959-8049(94)00413-y

Cited by 202 publications

(141 citation statements)

References 14 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…4 Further, some EWS do express relevant amount of GD2 making them vulnerable for CH14.18 monoclonal Ab treatment by recruiting NK cells via Ab-dependent cellular cytotoxicity and by C'-dependent cytotoxicity. [34][35][36] Both, application of IL-2 and infusion of targeting antibodies are treatment options, being evaluated in clinical trials after allogeneic HSCT to improve NK-mediated post transplant antitumor effects. 37 Accurate characterization of EWS including HLA I, GD2 and CD58 surface Ag expression may help to elucidate candidates suitable and those unsuitable for NK cell-based immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Schlegel

Feuchtinger

Nitschke-Gérard

et al. 2015

Bone Marrow Transplant

View full text Add to dashboard Cite

Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cellmediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Schlegel

Feuchtinger

Nitschke-Gérard

et al. 2015

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…Most of the patients were treated post transplant with the anti-neuroblastoma antibody ch 14.18. 18 Although we do not know the influence of the adjuvant immunotherapy with the monoclonal chimeric anti-GD2 antibody ch 14.18 on the long-term survival in some of our patients, we conclude that combined therapeutic approaches including chemo/radiotherapy and adjuvant therapeutic strategies, such as retinoic acid 31 or monoclonal antibodies 32 might hopefully improve the outcome in patients with high-risk neuroblastomas. However, larger controlled trials have to be performed to verify this conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…An adjuvant immunotherapy with the monoclonal antibody ch 14.18 was administered post transplant in 15 patients, as described by us. 18 Prior to autologous stem cell transplantation, only eight patients were in CR, whereas 10 patients were in PR or VGPR. After highdose chemotherapy, five of the 10 patients who were not in remission prior to transplant reached a CR and are alive without evidence of disease.…”

Section: Hematopoietic Reconstitution After Myeloablative Therapy Andmentioning

confidence: 99%

Isolation and transplantation of highly purified autologous peripheral CD34+ progenitor cells: purging efficacy, hematopoietic reconstitution and long-term outcome in children with high-risk neuroblastoma

Handgretinger

Lang

Ihm

et al. 2002

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:We have investigated the purging efficacy of positive selection of autologous mobilized CD34 ϩ peripheral stem cells in 22 children with high-risk neuroblastoma. CD34 ϩ cell selection was performed using the method of magnetic-activated cell sorting (MACS). The median purity of the CD34 ϩ cells post selection was 97.6% (range 81.7-99.7). For detection of contaminating neuroblastoma cells before and after CD34 ϩ selection, the chimeric anti-disialoganglioside GD2 antibody delta ch 14.18 was used. Prior to positive selection, various numbers of contaminating neuroblastoma cells were found in 17 patients. After positive CD34 ϩ cell selection, low numbers of neuroblastoma cells were only detectable in four patients. In 18 patients, high-dose chemotherapy was performed and the isolated CD34 ϩ cells were reinfused. In all patients, a rapid neutrophil recovery was seen with a median time to reach 0.5 × 10 9 /l neutrophils of 12 days (range 8-24 days). Nine of the 18 patients are free of progression with a median followup of 55 months (range 45-70 months). Two patients are alive with relapse, six patients died due to progression or relapse and one patient died due to secondary AML 10 months after transplant while in remission from neuroblastoma. In summary, we show that, through a highly effective positive selection method, a high purging efficacy can be obtained without compromising the hematopoietic reconstitution capacity of the graft. Bone Marrow Transplantation (2002) 29, 731-736.

show abstract

“…Replacement of the mouse V L chain by human Hum4V L in h/m or h/CDR scFvs decreased or completely eliminated the binding of antibodies from these human sera. Serum #2 exhibited a reactivity [43][44][45][46] others have been more immunogenic, with moderate 47 or significant immune responses. 48 -50 For a few murine antibodies, replacement of the C regions of the light and heavy chains by human C regions may not provide the solution to the problem of reducing HAMA responses in patients, because the V regions are potentially immunogenic and can lead to the development of antiidiotypic antibodies in patients.…”

Section: Analysis Of Immunogenicity Of Cc49 Scfvsmentioning

confidence: 99%

Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-tag-72 single-chain Fvs

Pavlínková

Colcher²,

Booth

et al. 2001

Int. J. Cancer

View full text Add to dashboard Cite

Key words: antibody engineering; antigen binding; antiidiotypic antibodies; monoclonal antibodies; single-chain antibodiesOne of the major complications in the clinical application of monoclonal antibodies can be the development of a human antimurine antibody (HAMA) response in patients. The HAMA can alter the clearance rate of the administered antibody from serum and can produce allergic reactions in patients. 1,2 The HAMA response can be directed against (i) mouse-specific determinants on the C region of heavy and light chains (antiallotypic Ig), (ii) isotypic determinants on the C region of heavy chains (antiisotypic Ig) and (iii) determinants specific for the administered mouse Ig (antiidiotypic Ig). 3 Many murine monoclonal antibodies (MAbs) have been humanized to overcome the HAMA response in patients. Two methods are being used for the genetic humanization of MAbs: chimerization, in which non-human C regions are replaced by C human regions 4 and complementary determining region (CDR) grafting, in which human CDRs are replaced by murine CDRs on the human framework regions. 5 The humanized MAbs are likely to be less immunogenic; however, murine CDRs are coding for non-human V region sequences and may still elicit an antiidiotypic response. 6 -9 Furthermore, CDR grafting could also generate new immunogenic epitopes. 6,9 The murine MAb CC49 recognizes tumor-associated glycoprotein (TAG-72), which is expressed by most human adenocarcinomas of the pancreas, colon, ovary, prostate, lung and esophagus 10 and is absent in most normal tissues. 11 Radiolabeled CC49 IgG has shown excellent tumor localization in several clinical trials. [12][13][14][15][16] However, one major complication of its clinical use is the development of a HAMA response in patients. 14 The incidence of HAMA response in gastrointestinal and ovarian cancer patients 1 month after exposure to the murine MAb CC49 was 70%. 17 Fifty-four percent of these patients developed an antiidiotypic response, and 12% developed an antiidiotypic response in the absence of antiallotypic and antiisotypic Ig. 17 However, CC49 MAb is less immunogenic than other murine MAbs that have been used in clinical trials. For example, 89%, 100% and 80% of patients receiving the MAbs B72.3, 17 G250 18 and CO17-1A, 19 respectively, developed the HAMA responses.In an attempt to modify the properties of the MAb CC49, genetically engineered CC49 single-chain antibody fragments (scFvs) have been developed. Compared with the corresponding IgG, scFvs exhibited a rapid blood clearance, excellent penetration into the tumor from the vasculature and higher tumor/normal tissue ratios in animal models. 20 -31 We have undertaken new studies to analyze the immunogenicity of CC49 scFvs using human sera obtained from patients with colon cancer treated by CC49 IgG in clinical trials. Three different CC49 scFv constructs (Fig. 1) were compared. The first construct was comprised of mouse CC49 variable light (V L ) and mouse CC49 variable heavy (V H ) regions connected by a 205C linker (m/m scF...

show abstract

A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma

Cited by 202 publications

References 14 publications

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Isolation and transplantation of highly purified autologous peripheral CD34+ progenitor cells: purging efficacy, hematopoietic reconstitution and long-term outcome in children with high-risk neuroblastoma

Effects of humanization and gene shuffling on immunogenicity and antigen binding of anti-tag-72 single-chain Fvs

Contact Info

Product

Resources

About