Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory requirements for preclinical development of bispecific antibodies ***

Dr. Anne Benzinger (Abschlußjahr: 2010)

Bispecific antibodies are a specific class of monoclonal antibodies targeting two different antigens. Their mode of action enables them to link two different cells, e.g. a tumour cell and an immune cell for tumour cell killing. Different formats of bispecific antibodies are in development primarily recruiting cytotoxic T-cells or non-lymphocytic immune cells. The trifunctional format of bispecific antibodies can recruit both cell types concomitantly and displays a unique concept of tumour cell killing and cancer immunization. In 2009, the first bispecific antibody (catumaxomab, active substance in Removab®) was approved for marketing in the European Union by the EMA for the treatment of malignant ascites.

Preclinical testing of medicinal products is a prerequisite for their application in humans. The goals of preclinical safety testing therefore include the identification of a safe initial dose for human application and the detection of possible toxicites as well as the identification of relevant parameters for monitoring during clinical trials. For preclinical development of bispecific antibodies regulatory guidance for biologicals, especially on monoclonal antibodies, is applicable. ICH S6 and the addendum ICH S6(R1) are the most relevant guidances suggesting a flexible, science based approach for designing a preclinical strategy for biotechnology-derived pharmaceuticals. Accordingly, the format of bispecific antibodies, their mode of action and the intended clinical indication determine the preclinical testing programme. Additionally, recommendations given by ICH S9 on the preclinical development of anticancer drugs should be considered as most bispecific antibodies are developed in cancer indications.

An important aspect in preclinical testing is to define relevant species for toxicity testing. The identification of relevant species is challenging for bispecific antibodies due to the fact that two different antigens are targeted, which both have to be present in animal species used for toxicity testing. This may require in most cases alternative approaches like homologous antibodies or transgenic animals as suggested by ICH S6 and ICH S6(R1) for toxicity testing.

According to the Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products, bispecific antibodies may be considered to be high risk products due to their mode of action, the epitopes targeted and the potential lack of relevant species. Therefore, preclinical studies to support first-in-man clinical trials should be designed in a way that potential factors for risks in human application can be identified.

The preclinical programme for first in man clinical trials with bispecific antibodies therefore consists of the following investigations: Primary and secondary pharmacodynamics studies investigating their mode of action, including desired and undesired effects using in vitro and an in vivo systems are required. Tissue cross-reactivity testing with human tissues has to be conducted to identify potential target tissues for toxicity. Basic pharmacokinetic data in relevant species should be analysed and toxicity testing in relevant species which can include safety pharmacology and local tolerance investigations is requested. The type of study (single-dose toxicity, dose-escalation toxicity, repeated-dose toxicity) to investigate potential toxicites of bispeficic antibodies is dependend on the duration of the clinical application and the indication to be treated. Furthermore, aspects of immunogenicity of bispecific antibodies in animals used for toxicity testing should be considerd.

Additional studies requested during the further clinical development of bispecific antibodies depend on the duration of application, the intended indication and the mode of action of a bispecific antibody: Further pharmacokinetic studies investigation absorption and distribution are required. The analysis of potential effects of drug-drug interactions may be necessary in cases when antibodies are combined with other drugs e.g. with chemotherapeutic agents in cancer therapy. Repeated toxicity studies of longer duration may be necessary according to the duration of clinical application and indication. If bispecific antibodies are not applied in end-stage cancer indications but with the intention to cure, reproductive toxicity studies are required. Cancerogenicity testing is usually not applicable for bispecific antibodies developed in late stage cancer indications but may be necessary if a cause for concern derives from the mode of action and the antibody is applied with the intention to cure a disease.

With numerous constructs in preclinical and clinical development, more experience with these unique products will be gained and specific aspects for development of bispecific antibodies regarding their format and mode of action may be addressed in regulatory guidance documents.

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