[Immunotoxins and immunocytokines]. / Immunotoxines et immunocytokines.

Cytokines and biological toxins represent two potent classes of biomolecules that have long been explored for their potential as therapeutics. Considerable side effects and poor pharmacokinetics frequently observed with both have limited their broad application. Recombinant protein engineering has allowed the construction of immunocytokines and immunotoxins that seek to exploit the advantageous properties of immunoglobulins to address these issues. Whole antibodies, antibody fragments, constant domains and derivatives have been fused genetically to a range of cytokines and toxins. This review considers the strategies that have been employed and the problems sought to be resolved in the clinical evaluation of this class of biotherapeutic.

TITLE: Immunotoxines et immunocytokines. ABSTRACT: Les cytokines et les toxines biologiques représentent deux classes de biomolécules qui ont longtemps été explorées pour leur potentiel thérapeutique. Des effets secondaires considérables et des mauvaises propriétés pharmacocinétiques sont fréquemment observés chez chacune d'elles, ce qui limite leur application. L'ingénierie des protéines recombinantes a permis la création d'immunocytokines et d'immunotoxines qui visent à utiliser les propriétés avantageuses des immunoglobulines, pour résoudre ces problèmes. Des anticorps entiers, des fragments d'anticorps, des domaines constants et des dérivés ont été génétiquement fusionnés à une gamme de cytokines et de toxines. Cette revue présente les stratégies déployées et les problèmes à résoudre au cours de l'évaluation clinique pour cette classe de biothérapeutiques.

Biological significance and targeting of c-Met tyrosine kinase receptor in cancer.

c-Met is a tyrosine kinase receptor largely described to be involved in cancer progression and metastasis. In such pathologic situation, many alterations of this receptor were noticed that include transcriptional overexpression, gene amplification, somatic or germline mutations and/or ligand dependent autocrine/paracrine loops. More recently it has also been suggested that c-Met would be involved in resistance to targeted therapies directed towards EGFR or angiogenesis. Major efforts from a large number of pharmaceutical companies are invested dedicated to evaluate the efficacy of either small molecule inhibitors or monoclonal antibodies directed against c-Met or its unique ligand HGF. A series of promising results from the first completed clinical trials indicated that compounds targeting c-Met have an acceptable toxicity profile and that efficacy was noticed in some treated patients. Non squamous NSCLC patients that express more often high levels of c-Met seemed to represent a most sensitive subset for and anti-c-Met/erlotinib therapy. Many Phase III trials are currently recruiting and a particular effort was performed in order to discover biomarkers associated with efficacy and patient selection. This review will provide an overview of the current knowledge on the c-Met axis for development of novel therapeutics in Oncology.

Insulin-like growth factor receptor type I as a target for cancer therapy.

After more than 20 years of extensive work, insulin-like growth factor receptor 1 (IGF-IR) is still an attractive target for drug development. Due to its close homology to insulin receptor, IGF-IR is of interest for antibody design while antibody great specificity allows to discriminate between the two receptors. Major efforts from a large number of pharmaceutical companies are invested to evaluate the efficacy of such molecules in human without so far an obvious success. Discovery of biomarkers associated with efficacy and patient selection is one of the main challenges that we will have to deal with in order to target the appropriate patient population that will most benefit anti-IGF-IR monoclonal antibody (Mab) and combined treatments. This review will provide an overview of the current knowledge on IGF-IR axis for development of novel therapeutics in Oncology.

Selection criteria for c-Met-targeted therapies: emerging evidence for biomarkers.

Extensive development of targeted therapies emphasize the critical need for biomarkers and major efforts have been engaged to identify screening, prognostic, stratification and therapy-monitoring markers. One of the challenges in translating preclinical studies into effective clinical therapies remains the accurate identification of a responsive subsets of patients. Studies on trastuzumab demonstrated that patient response could be specifically correlated with the amplification of the Her2 gene. However, for the EGF receptor, it has been more difficult to find the right stratification biomarker and recent data demonstrate that genetic alterations for the EGF receptor have to be considered. Taken together, these data underline the need for a deeper understanding of both targeted receptor and human disease to determine pathways that might be investigated during early clinical trials in order to define relevant biomarkers for patient selection. This article, dealing with the c-Met tyrosine kinase receptor, provides an overview of c-Met alterations observed in cancer and proposes approaches for stratification biomarker selection.

[Immunoconjugates, drug-armed antibodies to fight against cancer]. / Les immunoconjugués, anticorps << armés >> pour combattre le cancer.

Monoclonal antibodies constitute a growing class of therapeutic agents. They are classically used in combination with chemotherapeutic drugs for cancer treatment. The concept of coupling a cytotoxic agent to an antibody can be viewed as a means to confer a selectivity for tumoral cells to highly cytotoxic drugs which cannot be used in human, or a higher power to antibodies which have a low anti-tumoral activity on their own. Gemtuzumab ozogamicin is the only drug-armed antibody available on the market, for the treatment of acute myeloid leukaemia. Other immunoconjugates are currently under clinical development. The most used cytotoxic agents derive from calicheamicin, maytansin and auristatin, compounds which are 100 to 1 000 fold more toxic than the classical chemotherapeutic drugs. Today, we know that the efficacy of an immunoconjugate depends not only on the coupled cytotoxic agent, but also on the selected target, the coupling method and the linker.

[Monoclonal antibodies for treating infectious diseases]. / Anticorps thérapeutiques et maladies infectieuses.

Monoclonal antibodies (mAb) are attractive biologic drugs because of their specificity and well understood mechanisms of action. So far, most mAb have been developed for treating cancers or immunological disorders. However, the antibiotic resistance crisis, emerging viral diseases and bioterrorism have increased the development of anti-infectious mAb, for which more than twenty clinical trials are in progress to evaluate their safety and efficacy. The synergies obtained using combinations of anti-infectious mAb and small molecule drugs will certainly offer new opportunities for the treatment of infectious diseases.