Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms.

Grossbard, Michael L.; Lambert, JM; Goldmacher, V S; Spector, N; Kinsella, J; Eliseo, L; Coral, F; Taylor, J. Andrew; Blättler, Walter A.; Epstein, CL

doi:10.1200/jco.1993.11.4.726

Cited by 149 publications

(40 citation statements)

References 11 publications

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“…Another phase I trial of continuous infusion administration was conducted on 43 patients of B-cell neoplasms. In this trial, reported in 1993, two complete remissions and two partial remissions were observed [117]. Unfortunately, the following phase II trial, conducted on 16 NHL patients did not show any objective response.…”

Section: Anti-b4-brmentioning

confidence: 73%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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Antibody-based immunotoxins comprise an important group in targeted cancer therapeutics. These chimeric proteins are a form of biological guided missiles that combine a targeting moiety with a potent effector molecule. The targeting moiety is mostly a monoclonal antibody (MAb) or a recombinant antibody-based fragment that confers target specificity to the immunotoxin. The effector domain is a potent protein toxin of bacterial or plant origin, which, following binding to the target cells, undergoes internalization and causes cell death. Over time and following research progression, immunotoxins become better fitted to their purpose, losing immunogenic fragments and non-specific targeting moieties. Many immunotoxins have gone through clinical evaluation. Some of these have been shown to be active and work is progressing with them in the form of further clinical trials. Others, mostly developed in the previous century, failed to generate a response in patients, or even caused undesired side effects. This article reviews the antibody and protein-toxin based immunotoxins that were clinically evaluated up to the present day.

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Section: Anti-b4-brmentioning

confidence: 73%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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“…Although early studies showed that unmodified anti-CD19 antibodies induced B-cell depletion, their clinical efficacy was limited (8,15), and consequently, clinical trials focused on anti-CD19 immunotoxin conjugates (10,39). To maximize the cytotoxic potential of an unmodified antibody, multiple modes of tumor cell killing must be engaged: immune effector function (ADCC, ADCP, or CDC) and growth inhibition mechanisms (apoptosis or cell cycle arrest).…”

Section: Discussionmentioning

confidence: 99%

“…CD19 has been a focus of immunotherapy development for over 20 years, and several CD19-specific antibodies have been evaluated for the treatment of B-lineage malignancies in vitro, in mouse models, and in clinical trials. These have included unmodified anti-CD19 antibodies (8,9), antibody-drug conjugates (10)(11)(12), and bispecific antibodies targeting CD19 and CD3 (13) or CD16 (14) to engage cytotoxic lymphocyte effector functions. Although early clinical studies with murine unconjugated CD19 antibodies showed safety and responses in individual patients, these responses were not durable (15).…”

Section: Introductionmentioning

confidence: 99%

PotentIn vitroandIn vivoActivity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia

et al. 2008

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CD19 is a pan B-cell surface receptor expressed from pro-B-cell development until its down-regulation during terminal differentiation into plasma cells. CD19 represents an attractive immunotherapy target for cancers of lymphoid origin due to its high expression levels on the vast majority of non-Hodgkin's lymphomas and some leukemias. A humanized anti-CD19 antibody with an engineered Fc domain (XmAb5574) was generated to increase binding to Fc; receptors on immune cells and thus increase Fc-mediated effector functions. In vitro, XmAb5574 enhanced antibodydependent cell-mediated cytotoxicity 100-fold to 1,000-fold relative to an anti-CD19 IgG1 analogue against a broad range of B-lymphoma and leukemia cell lines. Furthermore, XmAb5574 conferred antibody-dependent cell-mediated cytotoxicity against patient-derived acute lymphoblastic leukemia and mantle cell lymphoma cells, whereas the IgG1 analogue was inactive. XmAb5574 also increased antibody-dependent cellular phagocytosis and apoptosis. In vivo, XmAb5574 significantly inhibited lymphoma growth in prophylactic and established mouse xenograft models, and showed more potent antitumor activity than its IgG1 analogue. Comparisons with a variant incapable of Fc; receptor binding showed that engagement of these receptors is critical for optimal antitumor efficacy. These results suggest that XmAb5574 exhibits potent tumor cytotoxicity via direct and indirect effector functions and thus warrants clinical evaluation as an immunotherapeutic for CD19 + hematologic malignancies.

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“…Approximately 90% of patients with epithelial carcinomas and 30% of the lymphoma patients have detectable human antimouse antibody and human antitoxin antibody after one cycle of immunotoxin therapy (1)(2)(3)(4). Although the formation of human antimouse antibody can be partly overcome by the use of humanized or chimeric monoclonal antibodies, the formation of antitoxin antibodies continues to represent a major problem.…”

Section: Introductionmentioning

confidence: 99%

Pretreatment with Rituximab Does Not Inhibit the Human Immune Response against the Immunogenic Protein LMB-1

Hassan

Williams-Gould

Watson

et al. 2004

Clinical Cancer Research

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Purpose: Rituximab, a humanized monoclonal antibody directed to the CD20 antigen present on B lymphocytes, could potentially abrogate the humoral immune response to murine monoclonal antibodies or immunotoxins by depleting antibody-producing B cells.Experimental Design: A Phase II study of LMB-1, an immunotoxin targeting the Lewis Y tumor antigen, in combination with rituximab was conducted to test the hypothesis that rituximab could abolish or diminish the development of human antibodies to LMB-1. Five patients were treated in this study and received 375 mg/m 2 rituximab on days 1 and 7 followed by 45 g/kg/day LMB-1 on days 10, 12, and 14. The development of human antibodies against LMB-1 was detected using a serum neutralization and ELISA.Results: All five of the patients had a total suppression of circulating CD20/CD19 B-cell population before the administration of the first dose of the immunotoxin. Before rituximab treatment, the mean percentage of CD20/CD19-positive B cells in the five treated patients was 19.8% (range, 4.5-29.8%) of the total peripheral lymphocytes. After two doses of rituximab, CD20/CD19-positive B lymphocytes constituted <0.1% of the total peripheral lymphocytes. Despite absent circulating antibody-producing B cells, before and during LMB-1 treatment, all of the patients developed neutralizing antibodies to the immunotoxin by day 21 of drug administration, which prevented retreatment.Conclusions: Even though rituximab caused complete depletion of circulating CD20/CD19-positive B cells, it had no effect in suppressing the human antibody response to LMB-1 and may be of limited utility in suppressing human antibody responses to other immunogenic proteins.

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Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms.

Cited by 149 publications

References 11 publications

Antibody-Based Immunotoxins for the Treatment of Cancer

Antibody-Based Immunotoxins for the Treatment of Cancer

PotentIn vitroandIn vivoActivity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia

Pretreatment with Rituximab Does Not Inhibit the Human Immune Response against the Immunogenic Protein LMB-1

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