Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy

Zhang, Qi; Chen, Guihua; Liu, Xinyuan; Qian, Qijun

doi:10.1038/sj.cr.7310143

Cited by 50 publications

(37 citation statements)

References 56 publications

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“…In recent years, several antibodybased therapies have progressed through regulatory approval by the Food and Drug Administration, and it is expected that many more will follow. 1 Immunotoxins are a category of immunoconjugate in which antibodies are joined to protein toxins. They exploit the precision of antibodies and the lethality of protein toxins to target and kill cancer cells expressing specific cell surface proteins.…”

Section: Introductionmentioning

confidence: 99%

A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity

Weldon

Xiang

Chertov

et al. 2009

Blood

153

191

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Immunotoxins based on Pseudomonas exotoxin A (PE) are promising anticancer agents that combine a variable fragment (Fv) from an antibody to a tumor-associated antigen with a 38-kDa fragment of PE (PE38). The intoxication pathway of PE immunotoxins involves receptor-mediated internalization and trafficking through endosomes/lysosomes, during which the immunotoxin undergoes important proteolytic processing steps but must otherwise remain intact for eventual transport to the cytosol. We have investigated the proteolytic susceptibility of PE38 immunotoxins to lysosomal proteases and found that cleavage clusters within a limited segment of PE38. We subsequently generated mutants containing deletions in this region using HA22, an anti-CD22 Fv-PE38 immunotoxin currently undergoing clinical trials for B-cell malignancies. One mutant, HA22-LR, lacks all identified cleavage sites, is resistant to lysosomal degradation, and retains excellent biologic activity. HA22-LR killed chronic lymphocytic leukemia cells more potently and uniformly than HA22, suggesting that lysosomal protease digestion may limit immunotoxin efficacy unless the susceptible domain is eliminated. Remarkably, mice tolerated doses of HA22-LR at least 10-fold higher than lethal doses of HA22, and these higher doses exhibited markedly enhanced antitumor activity. We conclude that HA22-LR advances the therapeutic efficacy of HA22 by using an approach that may be applicable to other PE-based immunotoxins. (Blood. 2009; 113:3792-3800) IntroductionMonoclonal antibodies, either alone or as immunoconjugates linked to other agents, have become valuable therapies for the targeted treatment of cancer. In recent years, several antibodybased therapies have progressed through regulatory approval by the Food and Drug Administration, and it is expected that many more will follow. 1 Immunotoxins are a category of immunoconjugate in which antibodies are joined to protein toxins. They exploit the precision of antibodies and the lethality of protein toxins to target and kill cancer cells expressing specific cell surface proteins. Any tumor-associated cell-surface antigen is a potential target for immunotoxins.A variety of plant, fungal, and bacterial toxins have been adapted for use with immunotoxins, including ricin, diphtheria toxin, and Pseudomonas exotoxin A (PE). 2,3 PE-based immunotoxins are currently in clinical trials for the treatment of CD22-expressing lymphomas and leukemias, as well as mesothelinexpressing solid tumors. 4,5 A phase 1 trial of the anti-CD22 PE immunotoxin BL22 had a high overall response rate of 81% but was particularly effective against drug-resistant hairy cell leukemia (HCL). 6 A phase 1 trial of the anti-CD25 PE immunotoxin LMB-2 showed a 23% response rate in patients with hematologic malignancies refractory to standard chemotherapy. 7 A phase 1 trial of the antimesothelin PE immunotoxin SS1P demonstrated minor but encouraging responses for treating solid tumors in patients with mesothelioma or ovarian cancer who had failed standard therapies....

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Section: Introductionmentioning

confidence: 99%

A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity

Weldon

Xiang

Chertov

et al. 2009

Blood

153

191

View full text Add to dashboard Cite

show abstract

“…1 The Food and Drug Administration has approved 30 antibody-based therapies, and it is expected that many more will follow. 2 Immunotoxins are a category of immunoconjugates in which antibodies are joined to protein toxins. They exploit the precision of antibodies and the lethality of protein toxins to target and kill cancer cells expressing specific cell surface proteins.…”

Section: Introductionmentioning

confidence: 99%

The improvement of an anti-CD22 immunotoxin

Kawa

Onda²,

Ho³

et al. 2011

mAbs

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“…13,14 Nonviral forms of delivery, particularly plasmid injection/electroporation, have successfully delivered functional full-length antibodies but have not yet approached the serum antibody levels required for efficacy. 12,15,16 Recent delivery of an anti-HER2 antibody by adenovirus showed significant inhibition of tumor growth; however, expression of the antibody was relatively transient likely due to immunogenicity and levels in the serum rapidly decreased.…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of an established A431 xenograft tumor by a full-length anti-EGFR antibody following gene delivery by AAV

Wykoff-Clary

Gross

et al. 2008

Cancer Gene Ther

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Therapeutic monoclonal antibodies continue to achieve clinical success for the treatment of many different diseases, particularly cancer. However, the production and purification of antibodies continues to be a time and labor-intensive process with considerable technical challenges. Gene-based delivery of antibodies may address this, via direct production within the host that achieves therapeutic levels. In this report, we validate the feasibility that gene-based delivery is a viable approach for efficacious delivery of antibodies in the preclinical and, presumably, clinical setting. We demonstrate high and sustained in vivo expression of the murine antihuman epidermal growth factor receptor antibody 14E1 following intramuscular delivery by adeno-associated virus (AAV) 2/1. Incorporating the Furin/2A technology for monocistronic expression of both heavy and light chains, we achieved sustained serum levels of full-length 14E1 peaking over 1 mg ml À1 in athymic nude mice. In the A431 xenograft tumor model, 14E1was capable of significantly inhibiting tumor growth and prolonging survival when AAV was administered prior to tumor challenge. Furthermore, 14E1 demonstrated significant antitumor efficacy against well-established tumors (B400 mm 3 ) when AAV was administered up to 20 days after tumor challenge. Here we demonstrate for the first time growth inhibition of a well-established tumor by a full-length antibody following delivery by AAV.

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Monoclonal antibodies as therapeutic agents in oncology and antibody gene therapy

Cited by 50 publications

References 56 publications

A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity

A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity

The improvement of an anti-CD22 immunotoxin

Growth inhibition of an established A431 xenograft tumor by a full-length anti-EGFR antibody following gene delivery by AAV

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