RESUMO
Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with beta-lactam-equipped targeting modules. A model study was first performed with beta-lactam conjugated to biotin. This conjugate efficiently and selectively modified the catalytic site lysine (LysH93) of mAb 38C2. We then conjugated a beta-lactam to a cyclic-RGD peptide to chemically program mAb 38C2 to target integrin receptors alpha(v)beta(3) and alpha(v)beta(5). The chemically programmed antibody bound specifically to the isolated integrin receptor proteins as well as the integrins expressed on human melanoma cells. This approach provides an efficient and versatile solution to irreversible chemical programming of aldolase antibodies.
Assuntos
Anticorpos Catalíticos/química , Química Farmacêutica/métodos , Frutose-Bifosfato Aldolase/síntese química , beta-Lactamas/síntese química , Anticorpos Catalíticos/metabolismo , Linhagem Celular Tumoral , Frutose-Bifosfato Aldolase/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , beta-Lactamas/metabolismoRESUMO
Irreversible chemical programming of monoclonal aldolase antibody (mAb) 38C2 has been accomplished with beta-lactam equipped mono- and bifunctional targeting modules, including a cyclic-RGD peptide linked to either the peptide (D-Lys(6))-LHRH or another cyclic RGD unit and a small-molecule integrin inhibitor SCS-873 conjugated to (D-Lys(6))LHRH. We also prepared monofunctional targeting modules containing either cyclic RGD or (D-Lys(6))-LHRH peptides. Binding of the chemically programmed antibodies to integrin receptors alpha(v)beta(3) and alpha(v)beta(5) and to the luteinizing hormone releasing hormone receptor were evaluated. The bifunctional and bivalent c-RGD/LHRH and SCS-783/LHRH, the monofunctional and tetravalent c-RGD/c-RGD, and the monofunctional bivalent c-RGD chemically programmed antibodies bound specifically to the isolated integrin receptor proteins as well as to integrins expressed on human melanoma M-21 cells. c-RGD/LHRH, SCS-783/LHRH, and LHRH chemically programmed antibodies bound specifically to the LHRH receptors expressed on human ovarian cancer cells. This approach provides an efficient, versatile, and economically viable route to high-valency therapeutic antibodies that target defined combinations of specific receptors. Additionally, this approach should be applicable to chemically programmed vaccines.
Assuntos
Anticorpos Biespecíficos/química , Anticorpos Monoclonais/química , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Linhagem Celular Tumoral , Frutose-Bifosfato Aldolase/química , Frutose-Bifosfato Aldolase/imunologia , Hormônio Liberador de Gonadotropina/química , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/química , Receptores LHRH/metabolismo , Receptores de Vitronectina/antagonistas & inibidores , Receptores de Vitronectina/metabolismo , beta-Lactamases/biossíntese , beta-Lactamases/imunologiaAssuntos
Anticorpos Catalíticos/química , Aptâmeros de Nucleotídeos/química , Animais , Anticorpos Catalíticos/uso terapêutico , Linhagem Celular , Movimento Celular , Reagentes de Ligações Cruzadas/química , Meia-Vida , Humanos , Camundongos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The 23rd Annual Antibody Engineering, 10th Annual Antibody Therapeutics international conferences, and the 2012 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, were held December 3-6, 2012 in San Diego, CA. The meeting drew over 800 participants who attended sessions on a wide variety of topics relevant to antibody research and development. As a prelude to the main events, a pre-conference workshop held on December 2, 2012 focused on intellectual property issues that impact antibody engineering. The Antibody Engineering Conference was composed of six sessions held December 3-5, 2012: (1) From Receptor Biology to Therapy; (2) Antibodies in a Complex Environment; (3) Antibody Targeted CNS Therapy: Beyond the Blood Brain Barrier; (4) Deep Sequencing in B Cell Biology and Antibody Libraries; (5) Systems Medicine in the Development of Antibody Therapies/Systematic Validation of Novel Antibody Targets; and (6) Antibody Activity and Animal Models. The Antibody Therapeutics conference comprised four sessions held December 4-5, 2012: (1) Clinical and Preclinical Updates of Antibody-Drug Conjugates; (2) Multifunctional Antibodies and Antibody Combinations: Clinical Focus; (3) Development Status of Immunomodulatory Therapeutic Antibodies; and (4) Modulating the Half-Life of Antibody Therapeutics. The Antibody Society's special session on applications for recording and sharing data based on GIATE was held on December 5, 2012, and the conferences concluded with two combined sessions on December 5-6, 2012: (1) Development Status of Early Stage Therapeutic Antibodies; and (2) Immunomodulatory Antibodies for Cancer Therapy.