Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck

Sauter, Alexander; Kloft, Charlotte; Gronau, Silke; Bogeschdorfer, F.; Erhardt, Thomas; Golze, Wolfram; Schroen, Carsten; Staab, Alexander; Riechelmann, Herbert; Hoermann, Karl

doi:10.3892/ijo.30.4.927

Cited by 36 publications

(50 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, CD44 is endogenously expressed at low levels in healthy tissues; 17 because of this expression, side effects still occur. 18,19 Antibody targeted therapies are effective in cancer treatments for three principal reasons: (1) The epitope recognized by the antibody is over-expressed on the tumor cell. (2) The antibody has better access to the tumor than to normal tissues that also express the epitope.…”

Section: Targeting To Cd44 With Anti-cd44 Antibodies or Hyaluronanmentioning

confidence: 99%

“…44 Anti-CD44 antibodies as targeting ligands for either radio-labels or anti-cancer chemotherapeutics in squamous cell carcinoma (SCC) of the head and neck (Table 2) stabilized disease progression in several patients. 18,19 A number of monoclonal antibodies capable of targeting SCC were identified. 45 The most specific antibody was developed as a clinical radioisotope carrier by converting it to a human/ mouse chimera that had a slightly lower half-life in circulation but a much higher capacity for cell lysis in a mouse xenograft tumor model.…”

Section: A Anti-cd44 Antibody Conjugatesmentioning

confidence: 99%

See 1 more Smart Citation

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

2008

View full text Add to dashboard Cite

The complex system involved in the synthesis, degradation, and binding of the high molecular weight glycosaminoglycan hyaluronic acid (hyaluronan or HA) provides a variety of structures that can be exploited for targeted cancer therapy. In many cancers of epithelial origin there is an up-regulation of CD44, a receptor that binds HA. In other cancers, HA in the tumor matrix is over-expressed. Both CD44 on cancer cells and HA in the matrix have been targets for anti-cancer therapy. Even though CD44 is expressed in normal epithelial cells and HA is part of the matrix of normal tissues, selective targeting to cancer is possible. This is because macromolecular carriers predominantly extravasate into the tumor and not normal tissue; thus CD44-HA targeted carriers administered intravenously localize preferentially into tumors. Anti-CD44 antibodies have been used in patients to deliver radioisotopes or mertansine for treatment of CD44 expressing tumors. In early phase clinical trials, patients with breast or head and neck tumors treated with anti-CD44 conjugates experienced stabilized disease. A dose-limiting toxicity was associated with distribution of the antibody-drug conjugate to the skin, a site in the body with a high level of CD44. HA has been used as a drug carrier and a ligand on liposomes or nanoparticles to target drugs to CD44 over-expressing cells. Drugs can be attached to HA via the carboxylate on the glucuronic acid residue, the hydroxyl on the Nacetylglucosamine, or the reducing end which are located on a repeating disaccharide. Drugs delivered in HA-modified liposomes exhibited excellent anti-tumor activity both in vitro and in murine tumor models. The HA matrix is also a potential target for anti-cancer therapies. By manipulating the interaction of HA with cell surface receptors, either by degrading it with hyaluronidase or by interfering with CD44-HA interactions using soluble CD44 proteins, tumor progression was blocked. Finally, cytotoxic drugs or pro-drug converting enzymes can be attached to the HA matrix to generate a cytotoxic fence around the tumor. This review describes how the complex interplay among cancer biology, the CD44-HA interaction, drug carriers and drug targeting has been used to improve anti-cancer therapies. As these approaches evolve, they hold forth the prospect of significantly improved targeted anti-cancer treatments. KeywordsAntibody; Biodistribution; Cancer; Chemotherapy; Drug-conjugate; EPR effect; Liposome; Polymer; Prodrug; Recombinant Protein The Biology of the CD44-Hyaluronan InteractionHyaluronan (HA) (Figure 1) is a high molecular weight glycosaminoglycan, extracellular matrix component essential for proper cell growth, organ structural stability, and tissue organization. The amount of HA in a tissue depends upon on a complex interplay among HA synthesis by HA synthases, 1 HA internalization by cell surface receptors, 2 Interference with the CD44-HA interaction by either targeting drugs to CD44, 14 targeting drugs to the HA matrix 15 or interfering with HA ma...

show abstract

Section: Targeting To Cd44 With Anti-cd44 Antibodies or Hyaluronanmentioning

confidence: 99%

Section: A Anti-cd44 Antibody Conjugatesmentioning

confidence: 99%

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

2008

View full text Add to dashboard Cite

show abstract

“…But new strategies and targeted therapy have been explored in the attempt to enhance survival rates in advanced HNSCC and especially unresectable HNSCC. Various experimental approaches have been investigated, as for example CD44v6 as a potential new target in HNSCC (7). Countless epigenetic and genetic events, including the aberrant expression and function of regulators of cell cycle, growth and signaling, motility, angiogenesis, and apoptosis are involved in pathogenesis of HNSCC and thus might be plausible targets for therapy.…”

Section: Discussionmentioning

confidence: 99%

“…For example, various studies have suggested potential prognostic values for p53 mutations, enhanced expression of epidermal growth factor (EGFR), transforming growth factor (TGF) ·, or cyclin D1 (4)(5)(6). More recently, novel CD44v6 targeting humanized antibodies were coupled to toxic substances in order to improve response rates in HNSCC (7).…”

Section: Head and Neck Squamous Cell Carcinoma (Hnscc)mentioning

confidence: 99%

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

Sauter¹

2011

Oncol Rep

View full text Add to dashboard Cite

Abstract. Squamous cell carcinoma of the head and neck (HNSCC) is the most common neoplasm arising in the upper aerodigestive tract. Unfortunately, the survival for this type of cancer has not improved significantly in the past 25 years. To enhance the survival rate multimodal therapy regimens have been set up. In these regimens chemotherapy plays a pivotal role in the majority of advanced cases. Transmembrane proteintyrosine kinases (PTK) are fundamental elements of the signal transduction. In consequence, they might be promising targets for cancer therapy. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukemia. But imatinib also has an inhibitory impact on the PTK receptor c-kit and on its PTK activity. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). The ECM is altered by matrix metalloproteinases (MMP). In this study, we incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin. After an incubation time of up to 10 days, we evaluated c-kit, MMP-2 and MMP-14 by ELISA techniques and immunohistochemical methods. Especially the combination of 7.5 μmol carboplatin with 30 μmol imatinib resulted in a significant decrease in MMP-2 expression in all observed cell lines (p<0.05). We did not demonstrate a significant alteration in c-kit expression by imatinib and carboplatin. We observed an increase in apoptosis in HNSCC cells by the combination of the two observed chemotherapeutic drugs. In all cell lines tested, expression of c-kit and MMP could be demonstrated. Our results indicate that MMP-2 expression was suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially one keeping in mind the moderate toxicity of imatinib.

show abstract

“…For example, various studies have suggested potential prognostic values for p53 mutations, enhanced expression of epidermal growth factor (EGFR), transforming growth factor-α (TGF-α) or cyclin D1 (4-6). More recently, novel CD44v6 targeting humanized antibodies were coupled with toxic substances in order to improve response rates in HNSCC (7,8).…”

Section: Introductionmentioning

confidence: 99%

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

et al. 2012

View full text Add to dashboard Cite

Abstract. Head and neck squamous cell carcinoma (HNSCC)is an aggressive epithelial malignancy. It is known to be the most common neoplasm appearing in the upper aerodigestive tract. The poor 5-year survival rate has remained unchanged in the last decades even though improved techniques in surgery, radiation and chemotherapy have been established. In contrast to the overall decreasing incidence of head and neck cancer in the US, the incidence of HPV-associated oropharyngeal cancer is increasing, indicating the importance of viral etiology. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). Matrix metalloproteinases (MMP) have been shown to play key roles in the remodeling of the ECM. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. But it also has an inhibitory impact, e.g., on the protein-tyrosine-kinase (PTK) receptor c-kit and on its PTK activity in HNSCC. In this study, we incubated the HNSCC cell lines HNSCC 11A and 14C and the p16-positive SCC line CERV196 with increasing concentrations of imatinib or carboplatin. After an incubation time of up to 10 days, we evaluated MMP-2 and -14 expression by ELISA techniques and immunohistochemistry. MMP-2 and -14 expression was demonstrated in all incubated tumor cell lines. Especially incubation with imatinib resulted in a significant decrease in MMP expression in incubated cell lines. Our results indicate that the expression of MMP-2 and -14 is suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially keeping in mind the moderate toxicity of imatinib.

show abstract

Pharmacokinetics, immunogenicity and safety of bivatuzumab mertansine, a novel CD44v6-targeting immunoconjugate, in patients with squamous cell carcinoma of the head and neck

Cited by 36 publications

References 29 publications

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

Contact Info

Product

Resources

About