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A novel fully human antitumour immunoRNase targeting ErbB2-positive tumours.

Borriello M, Laccetti P, Terrazzano G, D'Alessio G, De Lorenzo C - Br. J. Cancer (2011)

Bottom Line: Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer with success, can engender cardiotoxicity and a high fraction of patients is resistant to Trastuzumab treatment.Erb-hcAb-RNase retains the enzymatic activity of HP-RNase and specifically binds to ErbB2-positive cells with an affinity comparable with that of the parental Erb-hcAb.Its antitumour activity is more potent than that of the parental Erb-hcAb as the novel immunoconjugate has acquired RNase-based cytotoxicity in addition to the inhibitory growth effects, antibody-dependent and complement-dependent cytotoxicity of Erb-hcAb.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia Strutturale e Funzionale, Università Federico II, via Cinthia, Napoli 80126, Italy.

ABSTRACT

Background: ErbB2 is an attractive target for immunotherapy, as it is a tyrosine kinase receptor overexpressed on tumour cells of different origin, with a key role in the development of malignancy. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer with success, can engender cardiotoxicity and a high fraction of patients is resistant to Trastuzumab treatment.

Methods: A novel human immunoRNase, called anti-ErbB2 human compact antibody-RNase (Erb-hcAb-RNase), made up of the compact anti-ErbB2 antibody Erbicin-human-compact Antibody (Erb-hcAb) and human pancreatic RNase (HP-RNase), has been designed, expressed in mammalian cell cultures and purified. The immunoRNase was then characterised as an enzymatic protein, and tested for its biological actions in vitro and in vivo on ErbB2-positive tumour cells.

Results: Erb-hcAb-RNase retains the enzymatic activity of HP-RNase and specifically binds to ErbB2-positive cells with an affinity comparable with that of the parental Erb-hcAb. Moreover, this novel immunoRNase is endowed with an effective and selective antiproliferative action for ErbB2-positive tumour cells both in vitro and in vivo. Its antitumour activity is more potent than that of the parental Erb-hcAb as the novel immunoconjugate has acquired RNase-based cytotoxicity in addition to the inhibitory growth effects, antibody-dependent and complement-dependent cytotoxicity of Erb-hcAb.

Conclusion: Erb-hcAb-RNase could be a promising candidate for the immunotherapy of ErbB2-positive tumours.

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Related in: MedlinePlus

In vivo antitumour effects of Erb-hcAb-RNase and Trastuzumab. (A) In vivo antitumour effects of Erb-hcAb-RNase. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals were injected with Erb-hcAb-RNase (black squares), starting at day 14. Seven doses, each of 1.8 mg kg−1 of body weight, were administered at 72 h intervals i.p. In a parallel experiment, Erb-hcAb (black rhomboids) was administered at equimolar doses (1.3 mg kg−1) as indicated for Erb-hcAb-RNase, for comparison. (B) In vivo antitumour effects of Trastuzumab. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals (black rhomboides) were injected with Trastuzumab, starting at day 14. Seven doses, each of 2 mg kg−1 of body weight, were administered at 72 h intervals i.p.
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fig7: In vivo antitumour effects of Erb-hcAb-RNase and Trastuzumab. (A) In vivo antitumour effects of Erb-hcAb-RNase. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals were injected with Erb-hcAb-RNase (black squares), starting at day 14. Seven doses, each of 1.8 mg kg−1 of body weight, were administered at 72 h intervals i.p. In a parallel experiment, Erb-hcAb (black rhomboids) was administered at equimolar doses (1.3 mg kg−1) as indicated for Erb-hcAb-RNase, for comparison. (B) In vivo antitumour effects of Trastuzumab. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals (black rhomboides) were injected with Trastuzumab, starting at day 14. Seven doses, each of 2 mg kg−1 of body weight, were administered at 72 h intervals i.p.

Mentions: In order to compare the in vivo antitumour efficacy of this novel immunoagent with that of the parental Erb-hcAb, the effects of equimolar doses of Erb-hcAb and Erb-hcAb-RNase were tested in parallel on the same experimental model. In particular, to detect the differential potency of the two immunoagents, they were administered at lower doses than those used for peritumoural administrations of Erb-hcAb in the previous experiment (De Lorenzo et al, 2004b) when a dramatic reduction (96%) in tumour volume was observed. As shown in Figure 7, the treatment of mice bearing TUBO tumours with seven doses, at 72 h intervals, of 1.8 mg kg−1 of Erb-hcAb-RNase induced a significant reduction (about 50%) in tumour volume and showed more potent antitumour effects than those observed for the parental Erb-hcAb (doses of 1.3 mg kg−1).


A novel fully human antitumour immunoRNase targeting ErbB2-positive tumours.

Borriello M, Laccetti P, Terrazzano G, D'Alessio G, De Lorenzo C - Br. J. Cancer (2011)

In vivo antitumour effects of Erb-hcAb-RNase and Trastuzumab. (A) In vivo antitumour effects of Erb-hcAb-RNase. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals were injected with Erb-hcAb-RNase (black squares), starting at day 14. Seven doses, each of 1.8 mg kg−1 of body weight, were administered at 72 h intervals i.p. In a parallel experiment, Erb-hcAb (black rhomboids) was administered at equimolar doses (1.3 mg kg−1) as indicated for Erb-hcAb-RNase, for comparison. (B) In vivo antitumour effects of Trastuzumab. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals (black rhomboides) were injected with Trastuzumab, starting at day 14. Seven doses, each of 2 mg kg−1 of body weight, were administered at 72 h intervals i.p.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111160&req=5

fig7: In vivo antitumour effects of Erb-hcAb-RNase and Trastuzumab. (A) In vivo antitumour effects of Erb-hcAb-RNase. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals were injected with Erb-hcAb-RNase (black squares), starting at day 14. Seven doses, each of 1.8 mg kg−1 of body weight, were administered at 72 h intervals i.p. In a parallel experiment, Erb-hcAb (black rhomboids) was administered at equimolar doses (1.3 mg kg−1) as indicated for Erb-hcAb-RNase, for comparison. (B) In vivo antitumour effects of Trastuzumab. Tumour growth was followed in mice inoculated s.c. with 5 × 105 TUBO mammary carcinoma cells. Control animals (empty circles) were treated with sterile PBS solution. Treated animals (black rhomboides) were injected with Trastuzumab, starting at day 14. Seven doses, each of 2 mg kg−1 of body weight, were administered at 72 h intervals i.p.
Mentions: In order to compare the in vivo antitumour efficacy of this novel immunoagent with that of the parental Erb-hcAb, the effects of equimolar doses of Erb-hcAb and Erb-hcAb-RNase were tested in parallel on the same experimental model. In particular, to detect the differential potency of the two immunoagents, they were administered at lower doses than those used for peritumoural administrations of Erb-hcAb in the previous experiment (De Lorenzo et al, 2004b) when a dramatic reduction (96%) in tumour volume was observed. As shown in Figure 7, the treatment of mice bearing TUBO tumours with seven doses, at 72 h intervals, of 1.8 mg kg−1 of Erb-hcAb-RNase induced a significant reduction (about 50%) in tumour volume and showed more potent antitumour effects than those observed for the parental Erb-hcAb (doses of 1.3 mg kg−1).

Bottom Line: Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer with success, can engender cardiotoxicity and a high fraction of patients is resistant to Trastuzumab treatment.Erb-hcAb-RNase retains the enzymatic activity of HP-RNase and specifically binds to ErbB2-positive cells with an affinity comparable with that of the parental Erb-hcAb.Its antitumour activity is more potent than that of the parental Erb-hcAb as the novel immunoconjugate has acquired RNase-based cytotoxicity in addition to the inhibitory growth effects, antibody-dependent and complement-dependent cytotoxicity of Erb-hcAb.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Biologia Strutturale e Funzionale, Università Federico II, via Cinthia, Napoli 80126, Italy.

ABSTRACT

Background: ErbB2 is an attractive target for immunotherapy, as it is a tyrosine kinase receptor overexpressed on tumour cells of different origin, with a key role in the development of malignancy. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer with success, can engender cardiotoxicity and a high fraction of patients is resistant to Trastuzumab treatment.

Methods: A novel human immunoRNase, called anti-ErbB2 human compact antibody-RNase (Erb-hcAb-RNase), made up of the compact anti-ErbB2 antibody Erbicin-human-compact Antibody (Erb-hcAb) and human pancreatic RNase (HP-RNase), has been designed, expressed in mammalian cell cultures and purified. The immunoRNase was then characterised as an enzymatic protein, and tested for its biological actions in vitro and in vivo on ErbB2-positive tumour cells.

Results: Erb-hcAb-RNase retains the enzymatic activity of HP-RNase and specifically binds to ErbB2-positive cells with an affinity comparable with that of the parental Erb-hcAb. Moreover, this novel immunoRNase is endowed with an effective and selective antiproliferative action for ErbB2-positive tumour cells both in vitro and in vivo. Its antitumour activity is more potent than that of the parental Erb-hcAb as the novel immunoconjugate has acquired RNase-based cytotoxicity in addition to the inhibitory growth effects, antibody-dependent and complement-dependent cytotoxicity of Erb-hcAb.

Conclusion: Erb-hcAb-RNase could be a promising candidate for the immunotherapy of ErbB2-positive tumours.

Show MeSH
Related in: MedlinePlus