YM BioSciences :: Products :: Nimotuzumab

Science

EGFR-targeting drugs belong to a proven class of therapeutics that has been shown to improve patient outcomes when used as monotherapy or with conventional treatments such as radiation therapy and chemotherapy. EGFR is over-expressed in 24-80% of all solid tumors.^[1,2,3] Activation of the EGFR signaling pathway in cancer cells is linked with increased cellular proliferation, angiogenesis, metastasis and decreased apoptosis. EGFR over-expression correlates with poor response to treatment, disease progression and poor survival. Clinical and pre-clinical data show that anti-EGFR therapies inhibit these effects in vitro and in vivo.

Nimotuzumab is being developed to compete as best-in-class against the established class of EGFR-targeting drugs. This drug has displayed efficacy in numerous clinical trials, with anti-cancer activity that rivals the other EGFR-targeting antibody drugs, cetuximab and panitumumab. However, to YM's knowledge, in the more than 9,000 patients treated with nimotuzumab worldwide to date, very few have experienced Grade 4 radiation dermatitis or Grade 3/4 acneform rash, which is a severe and dose-limiting side-effect observed with all of the other antibodies and small molecules targeting the EGF tyrosine kinase signaling pathway. Reports of any severe incidents of the other side effects that are typical of EGFR-targeting molecules have been rare.

YM researchers have determined the underlying mechanism of action that may enable nimotuzumab to discriminate tumor cells from healthy cells, resulting in its improved side-effect profile. Unlike other EGFR-targeting antibody drugs, the attachment of nimotuzumab to EGFR occurs more readily when EGFR density is elevated, which occurs naturally in many cancers or which may be induced by radiation-containing therapies.^[4] In contrast, when EGFR density is low, such as in healthy tissue, the other antibodies will indiscriminately bind to the receptors naturally found in normal cells, resulting in the toxicities observed from this interaction with the healthy tissue. Nimotuzumab binding is transient thus sparing the healthy tissue and avoiding the associated severe toxicities. View the proposed mechanism of action animation.

¹ Temam S, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol 2007 Jun 1; 25(16): 2164-70
² Kim MA, et al. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology 2008 May; 52(6): 738-46
³ Ettinger D. Clinical Implications of EGFR Expression in the Development and Progression of Solid Tumors: Focus on Non-Small Cell Lung Cancer. The Oncologist 2006; 11: 358-73
⁴ Schmidt-Ullrich RK, et al. Altered expression of epidermal growth factor receptor and estrogen receptor in MCF-7 cells after single and repeated radiation exposures. Int J Radiat Oncol Biol Phys 1994; 29(4): 813-19

Manuscripts

	You B, et al. A dose-escalation phase I trial of nimotuzumab, an antibody against the epidermal growth factor receptor, in patients with advanced solid malignancies. Invest New Drugs 2010 May 8 (online)
	Choi HJ, et al. A phase I study of nimotuzumab in combination with radiotherapy in stages IIB–IV non-small cell lung cancer unsuitable for radical therapy: Korean results. Lung Cancer 2010 May 7 (online)
	Rojo F, et al. Pharmacodynamic Trial of Nimotuzumab in Unresectable Squamous Cell Carcinoma of the Head and Neck: A SENDO Foundation Study. Clin Cancer Res 2010 Apr 15; 16(8): 2474-2482
	Osorio-Rodriguez M, et al. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck. Cancer Biol Ther 2010 Mar; 9(5): 341-347
	Boland WK, Bebb G. Nimotuzumab: a novel anti-EGFR monoclonal antibody that retains anti-EGFR activity while minimizing skin toxicity. Expert Opin Biol Ther 2009 Sep; 9(9): 1199-1206
	Talavera A, et al. Nimotuzumab, an Antitumor Antibody that Targets the Epidermal Growth Factor Receptor, Blocks Ligand Binding while Permitting the Active Receptor Conformation. Cancer Res 2009 Jul; 69(14): 5851-5859
	Rudnick SI, Adams GP. Affinity and Avidity in Antibody-Based Tumor Targeting. Cancer Biother Radiopharm 2009 Apr; 24(2): 155-161
	Ramakrishnan MS, et al. Nimotuzumab, a promising therapeutic monoclonal antibody for treatment of tumors of epithelial origin. mAbs 2009 Jan/Feb; 1(1): 1-8
	Akashi Y, et al. Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 2008 Feb 26; 98(4): 749-755
	Crombet-Ramos T, et al. Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3. Cancer Biol & Ther 2006; 5(4): 375-379
	Crombet T, et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 2004; 22(9): 1646-1654
	Crombet T, et al. Pharmacological evaluation of humanized anti-epidermal growth factor receptor, monoclonal antibody h-R3, in patients with advanced epithelial-derived cancer. J Immunother 2003; 26(2): 139-148
	Crombet-Ramos T, et al. h-R3: TheraCIM: Humanized IgG₁ monoclonal antibody to epidermal growth factor receptor (EGFR): Treatment of Head and Neck Cancer, Treatment of Epithelial Tumors, Anti-EGFR mAb. Drugs of the Future 2003; 28(9): 847-853
	Crombet-Ramos T, et al. Antiproliferative, Antiangiogenic and Proapoptotic Activity of h-R3: A humanized anti-egfr antibody. Int J Cancer 2002; 101: 567-575
	Viloria-Petit A, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res 2001; 61: 5090-5101

Posters and Abstracts

	Gupta M, et al. Results from a pilot study of nimotuzumab with concurrent chemoradiation in patients with locally advanced squamous cell carcinoma of head and neck. J Clin Oncol 2010; 28(7s Suppl): Abstr 5565
	Babu KG, et al. An open-label, randomized, study of h-R3mAb (nimotuzumab) in patients with advanced (stage III or IVa) squamous cell carcinoma of head and neck (SCCHN): Four-year survival results from a phase IIb study. J Clin Oncol 2010; 28(7s Suppl): Abstr 5530
	Julka PK, et al. Feasibility and safety of combining nimotuzumab with temozolomide and radiotherapy in adult patients with glioblastoma: An Indian clinical experience. J Clin Oncol 2010; 28(7s Suppl): Abstr e12509
	Westphal M, et al. Current status of phase III anti-EGF-receptor antibody (OSAG-101) for newly diagnosed glioblastoma. J Clin Oncol 2010; 28(7s Suppl): Abstr 2056
	Fasih A, Reilly RM. ¹¹¹In-labeled nimotuzumab modified with nuclear localization sequences (NLS) for targeting Herceptin® resistant breast cancer cells. American Association for Cancer Research (AACR) Annual Meeting, 2010: Abstr 4551
	Jaramillo ML, et al. Nimotuzumab, a humanized anti-epidermal growth factor receptor antibody, interacts with EGFRvIII. American Association for Cancer Research (AACR) Annual Meeting, 2010: Abstr 1778
	Mutsaers AJ, et al. Combination treatment with metronomic cyclophosphamide and the EGFR monoclonal antibody nimotuzumab is efficacious and non-toxic in a preclinical model of advanced triple negative breast cancer. American Association for Cancer Research (AACR) Molecular Targets and Cancer Therapeutics, 2009: Abstr C49
	Viswanath L, et al. A Phase 2b, 4-arm open-label, randomized trial, to assess the safety and efficacy of concurrent hR3 monoclonal antibody against EGF-Receptor with chemo-radiation therapy or with radiation therapy in patients with advanced (stage III-IVa) inoperable head and neck cancer. American Society for Radiation Oncology (ASTRO) Annual Meeting, 2009
	Reddy BK, et al. A phase IIb 4-arm open-label randomized study to assess the safety and efficacy of h-R3 monoclonal antibody against EGFR in combination with chemoradiation therapy or radiation therapy in patients with advanced (stage III or IVA) inoperable head and neck cancer. J Clin Oncol 2009; 27(15s Suppl): Abstr 6041
	Boku N, et al. Phase I study of nimotuzumab, a humanized anti-epidermal growth factor receptor (EGFR) IgG1 monocloncal antibody in patients with solid tumors in Japan. J Clin Oncol 2009; 27(Suppl): Abstr e14574
	Garrido G, et al. Binding properties of the anti-EGFR monoclonal antibody, nimotuzumab, limit interaction with the EGFR in renal and epidermal cells. American Association for Cancer Research (AACR) 100th Annual Meeting, 2009: Abstr 2763
	Tikhomirov I, et al. Differences in clinical safety profiles of nimotuzumab and cetuximab, EGFR-targeting antibodies, as a consequence of divergent monovalent/bivalent binding profiles of these agents. European Society for Medical Oncology's 7th International Symposium on Targeted Anticancer Therapies, 2009: Abstr C02
	Cabanas R, et al. Long lasting survival in paediatric brain tumour patients treated with nimotuzumab, anti-epidermal growth factor receptor humanized monoclonal antibody. International Society of Pediatric Oncology (SIOP) 40th Annual Congress, 2008, Berlin
	Macias AI, et al. Preliminary results of a phase II clinical trial of the anti-EGFR monoclonal antibody nimotuzumab in combination with whole brain radiation therapy in patients diagnosed with advanced non-small cell lung cancer (NSCLC) and unresectable brain metastases. EORTC-NCI-AACR Annual Meeting, 2008, Geneva
	Crombet T, et al. Use of the humanized anti-EGFR MAb (nimotuzumab) and irradiation for the treatment of high grade glioma patients. EORTC-NCI-AACR Annual Meeting, 2008, Geneva
	Tikhomirov I, et al. Bivalent Binding Properties of Epidermal Growth Factor Receptor (EGFR) Targeted Monoclonal Antibodies: Factors Contributing to Differences in Observed Clinical Profiles. American Association for Cancer Research (AACR) Cancer Clinical Trials and Personalized Medicine, 2008: Abstr A36
	Bebb DG, et al. Preliminary results of an escalating dose phase I clinical trial of the anti-EGFR monoclonal antibody nimotuzumab in combination with external radiotherapy in patients diagnosed with stage IIb, III or IV non-small cell lung cancer unsuitable for radical therapy. J Clin Oncol 2008; 26(May 20 Suppl): Abstr 3037
	Bode U, et al. Phase III trial of nimotuzumab for the treatment of newly diagnosed diffuse intrinsic pontine gliomas in children and adolescents. J Clin Oncol 2008; 26(May 20 Suppl): Abstr 2058
	Rojo F, et al. Pharmacodynamic study of nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MAb), in patients with unresectable squamous cell carcinoma of the head and neck (SCCHN): A SENDO Foundation study. J Clin Oncol 2008; 26(May 20 Suppl): Abstr 6070
	Hilger RA, et al. Pharmacokinetic study of the humanized anti-EGF-receptor monoclonal antibody nimotuzumab in infant and adult patients. American Association for Cancer Research (AACR) 99th Annual Meeting, 2008: Abstr 211
	Reddy BK, et al. Nimotuzumab (h-R3) in Combination with Chemoradiotherapy and Radiotherapy in the Treatment of Squamous Cell Carcinoma of Head and Neck (SCCHN). Int J Radiat Oncol Biol Phys 2007; 69(3): Page S450, Abstr 2446
	Cabanas R, et al. Treatment of paediatric brain tumours with nimotuzumab, anti epidermal growth factor receptor humanized monoclonal antibody - preliminary report. International Society of Pediatric Oncology (SIOP) 39th Annual Congress, 2007: Abstr PJ-002
	Soriano JL, et al. Phase I clinical study of the humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody (Nimotuzumab) in combination with chemotherapy in patients with locally-advanced breast cancer. Preliminary results. ECCO 14 European Cancer Conference, 2007, Barcelona
	Hilger RA, et al. Pharmacokinetic Study of the Humanized Anti-EGF-Receptor Monoclonal Antibody Nimotuzumab in Combination with Gemcitabine in Patients (Pts) with Locally Advanced or Metastatic Pancreatic Cancer (PC). American Association for Cancer Research (AACR) 98th Annual Meeting, 2007: Abstr 926
	Bode U, et al. Final report of a phase II trial of nimotuzumab in the treatment of refractory and relapsed high-grade gliomas in children and adolescents. J Clin Oncol 2007; 25(18S, Part 1, June 20 Suppl): Abstr 2006
	Brade AM, et al. A single agent, phase I pharmacodynamic study of nimotuzumab (TheraCIM-h-R3) in patients with advanced refractory solid tumors. J Clin Oncol 2007; 25(18S, Part 1, June 20 Suppl): Abstr 14030
	Pendharkar D, et al. Feasibility of combining humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 (nimotuzumab) with chemotherapy-A study of toxicity profile and tolerance. J Clin Oncol 2007; 25(18S, Part 1, June 20 Suppl): Abstr 14151
	Talavera A, et al. Modeling the interaction between the anti-tumor antibody h-R3 and its target, the epidermal growth factor receptor. 11th Annual Meeting of the SBNet (Structural Biology Network), 2007, Sweden
	Crombet T, et al. Efficacy evaluation of the humanized anti-EGFR MAb h-R3 (nimotuzumab) in combination with radiotherapy in the treatment of patients with unresectable sqamous cell carcinoma of the head and neck. NCI-AACR-EORTC Meeting, 2006, Prague