Idioma:

Engineered Thio-Trastuzumab-DM1 Conjugate with an Improved Therapeutic Index to Target Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

JUNUTULA, Jagath R ; FLAGELLA, Kelly M ; MAI, Elaine ; LEWIS PHILLIPS, Gail D ; HIRARAGI, Hajime ; FUJI, Reina N ; TIBBITTS, Jay ; VANDLEN, Richard ; SPENCER, Susan D ; SCHELLER, Richard H ; POLAKIS, Paul ; SLIWKOWSKI, Mark X ; GRAHAM, Richard A ; PARSONS, Kathryn L ; HA, Edward ; RAAB, Helga ; BHAKTA, Sunil ; NGUYEN, Trung ; DUGGER, Debra L ; GUANGMIN LI

Clinical cancer research, 2010-10, Vol.16 (19), p.4769-4778 [Periódico revisado por pares]

Philadelphia, PA: American Association for Cancer Research

Texto completo disponível

Citações Citado por

Enviar para

Título:
Engineered Thio-Trastuzumab-DM1 Conjugate with an Improved Therapeutic Index to Target Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer
Autor: JUNUTULA, Jagath R ; FLAGELLA, Kelly M ; MAI, Elaine ; LEWIS PHILLIPS, Gail D ; HIRARAGI, Hajime ; FUJI, Reina N ; TIBBITTS, Jay ; VANDLEN, Richard ; SPENCER, Susan D ; SCHELLER, Richard H ; POLAKIS, Paul ; SLIWKOWSKI, Mark X ; GRAHAM, Richard A ; PARSONS, Kathryn L ; HA, Edward ; RAAB, Helga ; BHAKTA, Sunil ; NGUYEN, Trung ; DUGGER, Debra L ; GUANGMIN LI
Assuntos: Animals ; Antibodies, Monoclonal - chemistry ; Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal, Humanized ; Antineoplastic agents ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Breast Neoplasms - drug therapy ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Dose-Response Relationship, Drug ; Drug Design ; Drug Screening Assays, Antitumor ; Drug-Related Side Effects and Adverse Reactions ; Female ; Gynecology. Andrology. Obstetrics ; Humans ; Macaca fascicularis ; Mammary gland diseases ; Mammary Neoplasms, Experimental - drug therapy ; Maytansine - chemistry ; Maytansine - pharmacology ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Rats ; Rats, Sprague-Dawley ; Receptor, ErbB-2 - antagonists & inhibitors ; Receptor, ErbB-2 - chemistry ; Sulfhydryl Compounds - chemistry ; Sulfhydryl Compounds - pharmacology ; Trastuzumab ; Tumors
É parte de: Clinical cancer research, 2010-10, Vol.16 (19), p.4769-4778
Descrição: Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate. To generate thioTMAb-mpeo-DM1, one drug maytansinoid 1 (DM1) molecule was conjugated to an engineered cysteine residue at Ala114 (Kabat numbering) on each trastuzumab-heavy chain, resulting in two DM1 molecules per antibody. ThioTMAb-mpeo-DM1 retained similar in vitro anti-cell proliferation activity and human epidermal growth factor receptor 2 (HER2) binding properties to that of the conventional ADC. Furthermore, it showed improved efficacy over the conventional ADC at DM1-equivalent doses (μg/m(2)) and retained efficacy at equivalent antibody doses (mg/kg). An improved safety profile of >2-fold was observed in a short-term target-independent rat safety study. In cynomolgus monkey safety studies, thioTMAb-mpeo-DM1 was tolerated at higher antibody doses (up to 48 mg/kg or 6,000 μg DM1/m(2)) compared with the conventional ADC that had dose-limiting toxicity at 30 mg/kg (6,000 μg DM1/m(2)). The engineered thioTMAb-mpeo-DM1 with broadened therapeutic index represents a promising antibody drug conjugate for future clinical development of HER2-positive targeted breast cancer therapies.
Editor: Philadelphia, PA: American Association for Cancer Research
Idioma: Inglês

Links

Voltar para lista de resultados

Anterior Resultado 2 Avançar Ir para próxima página

Realização: Logos de Redes Sociais:

Engineered Thio-Trastuzumab-DM1 Conjugate with an Improved Therapeutic Index to Target Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Philadelphia, PA: American Association for Cancer Research

Buscando em bases de dados remotas. Favor aguardar.