Mechanisms of polymer degradation and erosion

The present application describes engineered antibodies, with three or more functional antigen binding sites, and uses, such as therapeutic applications, for such engineered antibodies.

Multivalent antibodies and uses therefor

Antibodies are engineered by replacing one or more amino acids of a parent antibody with non cross-linked, highly reactive cysteine amino acids. Antibody fragments may also be engineered with one or more cysteine amino acids to form cysteine engineered antibody fragments (ThioFab). Methods of design, preparation, screening, and selection of the cysteine engineered antibodies are provided. Cysteine engineered antibodies (Ab), optionally with an albumin-binding peptide (ABP) sequence, are conjugated with one or more drug moieties (D) through a linker (L) to form cysteine engineered antibody-drug conjugates having Formula I: Ab-(L-D)p I where p is 1 to 4. Diagnostic and therapeutic uses for cysteine engineered antibody drug compounds and compositions are disclosed.

Cysteine engineered antibodies and conjugates

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

Monomethylvaline compounds capable of conjugation to ligands

The present invention relates to optimized Fc variants, methods for their generation, and antibodies and Fc fusions comprising optimized Fc variants.

OPTIMIZED Fc VARIANTS AND METHODS FOR THEIR GENERATION

Drug response triggered by receptor activation arises from a chain of events that are regulated by many factors. Molecular changes associated with drug sensitization or tolerance are currently being elucidated on the molecular level, e.g. for adenylate cyclase coupled systems. Despite the complexity of the drug-response mechanism, simple empirical pharmaco-dynamic models on the basis of the law of mass action are widely applicable to describe drug-effect relationships. In combination with a pharmacokinetic model and suitable delay functions, such models are capable of simulating the complete time course of drug action in vivo. The predictive potential of the pharmacokinetic-pharmacodynamic models should prove useful in evaluating pharmaceutical formulations with controlled drug delivery.

Directed Drug Delivery

A. Pharmacodynamic and Pharmacokinetic Factors Influencing Directed Drug Delivery.- Pharmaceutics and the Evolving Technology of Drug Delivery-A Perspective.- Pharmacodynamic Considerations in the Development of New Drug Delivery Concepts.- Molecular Mechanisms of Drug Action and Pharmacokinetic-Pharmacodynamic Models.- The Therapeutic System: Therapeutic Implications of Rate-Controlled Drug Delivery.- B. Physiological and Biochemical Factors Influencing Directed Drug Delivery.- Gastrointestinal Barrier to Oral Drug Delivery.- Strategies for Drug Delivery Through the Blood-Brain Barrier.- The Dermal Barrier to Local and Systemic Drug Delivery.- C. Physical-Chemical Approaches to Directed Drug Delivery.- A Physical Approach to Drug Delivery.- Microparticulate Drug Carriers.- Biodegradable Poly(ortho Esters) as Drug Delivery Forms.- Macromolecules as Drug Delivery Systems.- D. Biological-Chemical Approaches to Directed Drug Delivery.- Monoclonal Antibody Mediated Drug Delivery and Antibody Toxin Conjugates.- Drug Delivery Via Cell-Surface Receptors.- Prodrugs: A Chemical Approach to Targeted Drug Delivery.- New Drug Delivery Systems: Physico-Chemical Considerations.- E. Analytical Aspects of Drug Delivery.- Analytical Aspects of Drug Delivery: An Important and Often Overlooked Problem.- Applications of Miniature Electrodes to Biomedical Studies.- The Use of Scintigraphic Methods for the Evaluation of Novel Delivery Systems.- Approaches to Improve Specificity and Sensitivity in Chromatography.

Arnold J. Repta

Papers

Directed Drug Delivery

Directed Drug Delivery: A Multidisciplinary Problem