Immunology and Biotherapies

Abstract

The convergence of advanced understanding of biology with chemistry has led to a resurgence in the development of antibody-drug conjugates (ADCs), especially with two recent product approvals. Design and development of ADCs requires the synergistic combination of the monoclonal antibody, the linker and the payload. Advances in antibody science has enabled identification and generation of high affinity, highly selective, humanized or human antibodies for a given target. Novel linker technologies have been synthesized and highly potent cytotoxic drug payloads have been created. As the first generation of ADCs utilizing lysine and cysteine chemistries moves through the clinic and into commercialization, second generation ADCs involving site specific conjugation technologies are being evaluated and tested. The latter aim to be better characterized and controlled, with wider therapeutic indices as well as improved pharmacokinetic-pharmacodynamic (PK-PD) profiles. ADCs offer some interesting physicochemical properties, due to conjugation itself, and to the (often) hydrophobic payloads that must be considered during their CMC development. New analytical methodologies are required for the ADCs, supplementing those used for the antibody itself. Regulatory filings will be a combination of small molecule and biologics. The regulators have put forth some broad principles but this landscape is still evolving.

Via Krishan Maggon

Abstract

Antibody-based therapy of various human malignancies has shown efficacy in the past 30 years and is now one of the most successful and leading strategies for targeted treatment of patients harboring hematological malignancies and solid tumors. Antibody–drug conjugates (ADCs) aim to take advantage of the affinity and specificity of monoclonal antibodies (mAbs) to selectively deliver potent cytotoxic drugs to antigen-expressing tumor cells. Key parameters for ADC include choosing the optimal components of the ADC (the antibody, the linker and the cytotoxic drug) and selecting the suitable cell-surface target antigen. Building on the success of recent FDA approval of brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®), ADCs are currently a class of drugs with a robust pipeline with clinical applications that are rapidly expanding. The more ADCs are being evaluated in preclinical models and clinical trials, the clearer are becoming the parameters and the challenges required for their therapeutic success. This rapidly growing knowledge and clinical experience are revealing novel modalities and mechanisms of resistance to ADCs, hence offering plausible solutions to such challenges. Here, we review the key parameters for designing a powerful ADC, focusing on how ADCs are addressing the challenge of multiple drug resistance (MDR) and its rational overcoming.

Via Krishan Maggon

PASADENA, Calif., April 20, 2015 /PRNewswire/ -- Meditope Biosciences, Inc., a biotechnology company developing novel antibody-based products using its proprietary technology, today announced presentation of data demonstrating the use of its SnAP technology platform for the development of antibody-drug conjugates (ADCs). The data were presented in an abstract at the AACR Annual Meeting 2015, taking place April 18-22 in Philadelphia.

 

Scientists at the company demonstrated the successful transplantation of the meditope binding site to several antibodies. Meditope-peptides of different affinities were then selected by rational design and fine-tuned according to the requirements of specific application. For ADC development, data show that the meditope-peptides are conjugated with cytotoxic payloads and the higher the affinity of the meditope-peptide-drug conjugate for the antibody, the higher the complex's cytotoxic potential against antigen-positive tumor cells.

Via Krishan Maggon

August 15, 2014 | Lutz Nuhn, PhD | Institute of Organic Chemistry, Johannes Gutenberg-University, Duesbergweg 10-14, D-55099 Mainz (Germany)…

 

The comparison of antibody-polymer conjugates of different topologies (“cross-linked” versus “star-like”) demonstrated that the well-defined constructs derived from maleimide-endgroup modified HPMA copolymers prevent non-specific interaction with immune cells and guarantee antibody-mediated active delivery to the target cell type. By using aDEC205 as antibody the delivery of multifunctionalizable HPMA carrier polymers to CD8+ dendritic cells is possible enabling novel application especially for immontherapeutic purposes. [5] Considering the numerous possibilities of equipping the HPMA carriers with further tumor relevant antigens and immunostimulants, as recently shown by ligation of selective MUC1-derived glycopeptides antigens to HPMA block copolymers, [3] a combination with aDEC205 mediated delivery would guarantee antigen cross-presentation to CD8+ T cells and differentiation into specific cytotoxic T cells (CTLs) for selective antitumor response on a cellular level. As a result, such well-defined multifunctional HPMA-aDEC205 polymer conjugates can be considered as novel vaccine delivery platform towards antitumor immunity.

Via Krishan Maggon