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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

Effects of the RNase inhibitor (RI) on the enzymatic activity of the immunoRNases (IR). Inhibition by RI of the catalytic activity of the anti-ErbB2 Erb-hcAb-RNase (circles) or Erb-hRNase (rhomboids) was measured at increasing RI/IR ratios.
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fig3: Effects of the RNase inhibitor (RI) on the enzymatic activity of the immunoRNases (IR). Inhibition by RI of the catalytic activity of the anti-ErbB2 Erb-hcAb-RNase (circles) or Erb-hRNase (rhomboids) was measured at increasing RI/IR ratios.

Mentions: As shown in Figure 3, the novel chimeric protein was found to be susceptible of inhibition by RI, even though it was found to be less sensitive than the monomeric immunoRNase. Indeed, the new ImmunoRNase retains a residual 30% of the enzymatic activity even at a cRI/IR ratio of about 5, whereas the activity of the monomeric IR is completely inhibited at a cRI/IR ratio of about 1 (Figure 3).


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)

Effects of the RNase inhibitor (RI) on the enzymatic activity of the immunoRNases (IR). Inhibition by RI of the catalytic activity of the anti-ErbB2 Erb-hcAb-RNase (circles) or Erb-hRNase (rhomboids) was measured at increasing RI/IR ratios.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Effects of the RNase inhibitor (RI) on the enzymatic activity of the immunoRNases (IR). Inhibition by RI of the catalytic activity of the anti-ErbB2 Erb-hcAb-RNase (circles) or Erb-hRNase (rhomboids) was measured at increasing RI/IR ratios.
Mentions: As shown in Figure 3, the novel chimeric protein was found to be susceptible of inhibition by RI, even though it was found to be less sensitive than the monomeric immunoRNase. Indeed, the new ImmunoRNase retains a residual 30% of the enzymatic activity even at a cRI/IR ratio of about 5, whereas the activity of the monomeric IR is completely inhibited at a cRI/IR ratio of about 1 (Figure 3).

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