Prodrug-Activating Chain Exchange (PACE) converts targeted prodrug derivatives to functional bi- or multispecific antibodies.

Driven by the potential to broaden the target space of conventional monospecific antibodies, the field of multi-specific antibody derivatives is growing rapidly. The production and screening of these artificial proteins entails a high combinatorial complexity. Antibody-domain exchange was previously shown to be a versatile strategy to produce bispecific antibodies in a robust and efficient manner. Here, we show that the domain exchange reaction to generate hybrid antibodies also functions under physiological conditions. Accordingly, we modified the exchange partners for use in therapeutic applications, in which two inactive prodrugs convert into a product with additional functionalities. We exemplarily show the feasibility for generating active T cell bispecific antibodies from two inactive prodrugs, which per se do not activate T cells alone. The two complementary prodrugs harbor antigen-targeting Fabs and non-functional anti-CD3 Fvs fused to IgG-CH3 domains engineered to drive chain-exchange reactions between them. Importantly, Prodrug-Activating Chain Exchange (PACE) could be an attractive option to conditionally activate therapeutics at the target site. Several examples are provided that demonstrate the efficacy of PACE as a new principle of cancer immunotherapy in vitro and in a human xenograft model.

Ingredients tracking of cosmetic formulations in the skin: a confocal Raman microscopy investigation.

PURPOSE: Confocal Raman microspectroscopy (CRM) was used to follow the absorption of retinol into the skin and to track the absorption of ingredients in topically applied formulations. METHOD: Three surfactants, PEG20C12, PEG20C18:1 (hydrophilic) and PEG6C18:1 (lipophilic), were used in preparing three o/w emulsions and three surfactant solutions all containing retinol. Quantitative retinol penetration studies for 24 h were carried out using Franz diffusion cells. CRM was used to follow the skin penetration of retinol, oil and water and also to study a possible modification of the lipid skin barrier in the stratum corneum (SC) using the ratio of I(2880)/I(2850). RESULTS: The oily surfactant solution containing PEG6C18:1 and dodecane showed the highest retinol penetration rate. This appears to be related both to the short polar head group of the surfactant and to the effect of dodecane on skin lipids. All the surfactant solutions showed a higher penetration rate compared with the corresponding emulsions. CRM measurements showed that the ratios of I(2880)/I(2850) were significantly modified using surfactant solutions. CONCLUSIONS: Penetration behavior appeared to be dependent on the surfactant used in the formulation. CRM associated to the Franz cell method gives new insights on permeation of drug related to vehicle or ingredients.

Confocal Raman microspectroscopy of the skin.

Confocal Raman spectroscopy is a technique with considerable potential for the non-invasive study of biological tissues and skin samples in vitro or in vivo. It can be used to study skin physiology and possible pathological conditions and to obtain data about molecular composition and the structure of skin, for example, water content, moisturization and changes in the skin barrier function can all be observed. In-depth measurements also allow biopharmaceutical studies, such as analyzing the rate of penetration of a drug and the biochemical changes that may be induced by an applied formulation. Confocal Raman microspectroscopy is now at such a stage of refinement that it opens up new vistas. The big leap forward in its ease of use enables this technology to be used as an analytical method by more and more non-specialist laboratories. This review gives an overview of the state of the art of this technology by presenting an update on the principles of Raman spectroscopy and then by looking at examples of new developments in in vivo and in vitro applications.

Topical delivery of cosmetics and drugs. Molecular aspects of percutaneous absorption and delivery.

Percutaneous penetration/permeation is a useful tool for obtaining qualitative and/or quantitative information on the amount of a drug, a cosmetic substance, or any chemical that may enter a skin compartment or the systemic circulation of the human body for pharmaceutical or cosmetic purposes, or for toxicological studies. In the latter case, the extent entering can then be taken into consideration in order to calculate the margin of safety using the NOAEL (No Observed Adverse Effect Level) of an appropriate repeated dose toxicity study with the respective substance. This paper is a short overview of various aspects of skin penetration/permeation of drugs or cosmetic agents. The literature reports numerous studies on skin structure and skin properties influencing drug/cosmetic agent permeation profiles and kinetic parameters. The extensive research concerning the skin structure for determining the key parameters of the penetration/permeation process is therefore described first. Mathematical models of the skin absorption process for a drug are then discussed. Finally new developments in pharmaceutical and cosmetic fields to enhance drug permeation or to modify the stratum corneum structure are considered.