ADC
ANTIBODY-DRUG CONJUGATE
Unique DMPK Study Methodology to Accelerate
the Development & Application of ADCs
Antibody-drug conjugates (ADCs) represent emerging biotherapeutics that are composed of cytotoxic payloads conjugated to a monoclonal antibody (mAb) via a chemical linker. Characterization of the ADME properties of ADCs is much more challenging. Based on our experience in ADC project research, we divided the ADC DMPK study into four main aspects: ADME, in vitro DDI, PK/TK and bioanalysis. These four aspects have their own emphasis in the discovery, preclinical and clinical stages. The WuXi AppTec DMPK team will propose a pharmacokinetic study strategy and study method for each ADC project based on their structures to accelerate the development and application of ADCs.
The team had successfully supported 21 ADC projects, including 13 ADC projects for IND. In this process, we have accumulated rich experience and formed a unique methodology for ADC pharmacokinetic studies, which can help customers quickly advance their ADC drug development projects.
ADC Pharmacokinetic Study Services
ADC
· Plasma or serum stability
· In vitro payload release study
· In vivo PK study in pharmacodynamic and toxicological species
· ADME study of radiolabeled ADCs in animals
· In vivo identification of payload-related metabolites released by ADCs
Payload
· Plasma protein binding
· CYP450 enzyme inhibition and induction
· CYP450 enzyme phenotyping
· Transporter substrate and inhibition assessment
· In vivo PK study in pharmacodynamic and toxicological species
· ADME study of radiolabeled payloads in animals
Pharmacokinetic Study Contents
Challenges in ADC Pharmacokinetic Studies
High Difficulty
ADC is a combination of large and small molecules and requires pharmacokinetic studies of both molecules.
ADC is a novel drug with very limited understanding of its ADME properties.
The payload is highly toxic, so human radiolabeled ADME studies cannot be performed for ADCs
High Significance
The efficacy of ADCs is directly related to the release and concentration of the payload in the target tissue.
The toxicity of ADCs is directly related to the release and concentration of the payload in the non-target tissue.
The selection of toxicological species of ADCs is related to the similarity of the payload in metabolism in both humans and animals.
The DDI of ADCs is directly related to the exposure as well as metabolism and elimination of the payload.
Key Study Capabilities
Investigation of the payload release from ADCs using different in vitro models.
Detection of the payload and related metabolites released from ADCs using non-targeted LC/HRMS.
Determination of total antibody and ADC drug concentration by LBA technique to support the ADC PK study in vivo.
DAR analysis using HRMS.
Study on tissue distribution of ADCs using QWBA technique.
ADC Pharmacokinetic Study Strategies
Our Strengths
Customer First and Customer Centric
We have a specialized and dedicated service model. Each client will be connected to a dedicated study director who will provide comprehensive management services for the pharmacokinetic project from drug discovery to the clinical phase.
Extensive Experiences and Custom-Designed ADC Study Strategies
With years of accumulated experience, we provide customized designs for pharmacokinetic study strategies for our customers' new molecules based on flexible study concepts with rapid optimization and adjustment.
Comprehensive Capacities and the Executive Capability to Successfully Respond to the Challenges in ADC Studies
We are capable of carrying out both small and large molecule DMPK studies, comprehensive ADC bioanalysis, metabolite identification of payloads in vivo and in vitro, and radiolabeled ADME studies.Case Study
Committed to accelerating drug discovery and development, we offer a full range of discovery screening, preclinical development, clinical drug metabolism, and pharmacokinetic (DMPK) platforms and services. With research facilities in the United States (New Jersey) and China (Shanghai, Suzhou, and Nanjing), a team of 1,000+ scientists and over ten years of experience in Investigational New Drug (IND) application, our DMPK Service Department are serving 1,000+ global clients, and have supported 600+ IND applications successfully.
Take pre-clinical PK/TK study of TIVDAK (Tisotumab vedotin-tftv) as an example. TIVDAK, the latest ADC approved by the FDA (marketed on September 20, 2021), targets Tissue Factor (TF), is used for the treatment of adult patients with recurrent or metastatic cervical cancer that progresses during or after chemotherapy. The antibody to TIVDAK is Tisotumab, an unmarketed antibody drug. The payload is MMAE, which has been used in many ADCs (ADCETRIS, POLIVY and PADCEV). The linker is a commonly used cleavable valine-citrulline structure.
The preclinical pharmacokinetic study of TIVDAK was summarized according to the published literature.
1. Payload release study: Plasma stability was mainly investigated.
2. In vivo PK/TK studies of ADC and payload: According to the homology of amino acid sequence and tissue cross reaction results of monoclonal antibodies, the relevant animal species selected was cynomolgus monkey. So, PK/TK studies on ADC and monoclonal antibodies were carried out in cynomolgus monkeys. Tissue distribution of radiolabeled monoclonal antibodies were carried out in cynomolgus monkeys and tumor-bearing models. Tissue distribution of radiolabeled ADC was carried out in tumor-bearing models. The PK/TK studies of MMAE were carried out in rats and cynomolgus monkeys. The mass balance study of MMAE was carried out in rats.
3. In vitro ADME studies of payload: The plasma protein binding, metabolite identification and CYP450 reaction phenotyping, transporter substrate and inhibition studies were mainly investigated.
[1] Drug Metab Dispos 44: 617-623, May 2016;
[2] https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761208Orig1s000MultidisciplineR.pdf
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