Monoclonal antibody lead characterization: in vitro and in vivo methods.

This chapter describes in vitro and in vivo methods to characterize a lead monoclonal antibody candidate in the drug discovery setting. Approaches to characterize monoclonal antibody specificity, heavy and light chain composition, and antibody mode of action including the ability to mediate secretion of effector molecules, inhibit cell proliferation, induce apoptosis, or elicit antibody effector function are described. ELISA and flow cytometry based methods, as well as in vitro assays to assess for cell proliferation, ADCC, and CDC are detailed.

Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease.

The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes.

Surrogate approaches in development of monoclonal antibodies.

When cross-reactivity of a lead antibody across species is limited, antibody development programs require the generation of surrogate molecules or surrogate animal models necessary for the conduct of preclinical pharmacology and safety studies. When surrogate approaches are employed, the complexities and challenges for translation of preclinical safety and efficacy results to the clinic are undoubtedly enhanced. Because there are no currently established criteria or regulatory guidance regarding the application of surrogate approaches, a science-based strategy for translation of preclinical information to the clinic is vital for effective development of the lead antibody.

Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies.

Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.

Translational strategies for development of monoclonal antibodies from discovery to the clinic.

Successful strategies for the development of monoclonal antibodies require integration of knowledge with respect to target antigen properties, antibody design criteria such as affinity, isotype selection, Fc domain engineering, PK/PD properties and antibody cross-reactivity across species from the early stages of antibody development. Biophysical measurements are one of the critical components necessary for the design of effective translational strategies for lead selection and evaluation of relevant animal species for preclinical safety and efficacy studies. Incorporation of effective translational strategies from the early stages of the antibody development process is a necessity; when considered it not only reduces development time and cost, but also fosters implementation of rational decision-making throughout all phases of antibody development.

CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma.

Purpose: Advanced melanoma is a highly drug-refractory neoplasm representing a significant unmet medical need. We sought to identify melanoma-associated cell surface molecules and to develop as well as preclinically test immunotherapeutic reagents designed to exploit such targets.

Experimental Design And Results: By transcript profiling, we identified glycoprotein NMB (GPNMB) as a gene that is expressed by most metastatic melanoma samples examined.

A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis.

PDGF-B is of central importance in mesangioproliferative diseases. PDGF-D, a new PDGF isoform, like PDGF-B, signals through the PDGF betabeta-receptor. The present study first determined that PDGF-D is mitogenic for rat mesangial cells and is not inhibited by a PDGF-B antagonist.