Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin

Ramakrishnan, M. S.; Eswaraiah, Anand; Crombet, Tania; Piedra, Patricia; Saurez, Giselle; Iyer, Harish; Arvind, A.S.

doi:10.4161/mabs.1.1.7509

Cited by 208 publications

(175 citation statements)

References 16 publications

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“…It has been concluded that a potential correlation exists between dose-dependent skin toxicity effects and the affinity constant of therapeutic anti-EGFR antibodies. 42 Accordingly, nimotuzumab, which shows lower binding affinity than other anti-EGFR antibodies, has not demonstrated any toxic cutaneous effect in numerous clinical trials. 43 In another approach, the Probody TM Platform was developed to improve the safety profile of cetuximab.…”

Section: Discussionmentioning

confidence: 99%

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Yang

Guo

Mao³

et al. 2015

mAbs

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These authors contributed equally to this work.Keywords: monoclonal antibody, EGFR, panitumumab, ADCC, target-selective activation, Probody TM Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; mAb, monoclonal antibody; EGFR, epidermal growth factor receptor; uPA, urokinase-type plasminogen activator; TKI, tyrosine kinase inhibitor; IgG, Immunoglobulin G; ELISA, enzyme-linked immunosorbent assay; SPR, surface plasmon resonance; CI, confidence interval; LC, light chain; HC, heavy chain; EGFR VIII, EGFR Type III Variant; CRC, colorectal cancer; ECD, extracellular domain; SEC, size exclusion chromatography; CCK-8, Cell Counting Kit 8YunPanitumumab, as a commercially available antibody, is an effective anticancer therapeutic against epidermal growth factor receptor (EGFR), although it exerts weak antibody-dependent cell-mediated cytotoxicity (ADCC) activity owing to its IgG2 nature. Here, we firstly engineered panitumumab by grafting its variable region into an IgG1 backbone. The engineered panitumumab (denoted as Pan) retained binding activity identical to the parental antibody while exhibiting stronger ADCC activity in vitro and more potent antitumor effect in vivo. To further enhance the target selectivity of Pan, we generated Pan-P by tethering an epitope-blocking peptide to Pan via a tumor-specific protease selective linker. Pan-P showed almost 40-fold weaker affinity compared with Pan, but functional activity was restored to a similar extent as Pan when Pan-P was selectively activated by urokinase-type plasminogen activator (uPA). More importantly, targeted localization of Pan-P was observed in tumor samples from colorectal cancer (CRC) patients and tumor-bearing nude mice, strongly indicating that specific activation also existed ex vivo and in vivo. Furthermore, Pan-P also exhibited effective in vivo antitumor potency similar to Pan. Taken together, our data evidence the enhanced antitumor potency and excellent target selectivity of Pan-P, suggesting its potential use for minimizing on-target toxicity in anti-EGFR therapy.

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Section: Discussionmentioning

confidence: 99%

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Yang

Guo

Mao³

et al. 2015

mAbs

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“…A previous study concluded that stronger binding clearly leads to higher toxicities among EGFR-targeted antibodies. 44 Thus, PanP-DM1 has the potential to achieve desired tolerability profile with less binding on normal cells than other conventional anti-EGFR ADCs.…”

Section: Discussionmentioning

confidence: 99%

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

Yang¹,

Guo²,

Chen³

et al. 2016

mAbs

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Antibody-drug conjugates (ADCs) have exhibited potent clinical benefits in cancer therapy. However, development of ADCs against epidermal growth factor receptor (EGFR) has limitations because of wide expression of EGFR in both normal and tumor tissues. Previously, we developed an anti-EGFR proteaseactivated antibody (pro-antibody), termed as PanP, which remains inert against EGFR until activated by tumor-specific protease. Herein, we for the first time report a new class of pro-antibody-drug conjugate (PDC) against EGFR, denoted as PanP-DM1. It has been designed to selectively target the EGFRoverexpressing tumor cells and exert greater anti-tumor activity compared with PanP. Our data showed that PanP-DM1 also could be selectively activated by tumor-specific protease 'uPA'. Furthermore, activated PanP-DM1 was potently cytotoxic against EGFR-overexpressing tumor cell lines in vitro. Crucially, our data indicated that PanP-DM1 was significantly more effective in eradicating EGFR-overexpressing tumors in vivo. Additionally, toxicity was preliminarily evaluated in mice as measured by body weight loss. In summary, our study suggests that PanP-DM1, a novel pro-antibody-drug conjugate, has cancer-selectivity, efficacy and safety profile that supports its potential use for EGFR-overexpressing tumors.

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“…The EGFR mAbs zalutumumab and nimotuzumab (Biacon) both inhibit ligand-binding and EGFR-driven proliferation. Zalutumumab does so with high affinity (23), whereas nimotuzumab blocks EGF binding with low affinity (24).…”

Section: Antibody Generation and Conjugationmentioning

confidence: 99%

High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

Goeij

Satijn

Freitag

et al. 2015

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TFspecific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR-and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach.

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Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin

Cited by 208 publications

References 16 publications

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

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