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ADC Preclinical Integrated Research Plan
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2022-09-03
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In the formulation of ADC preclinical integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers.

Solutions

There is no fixed research protocol for the research of ADC drugs. Due to the differences in conjugation strategies and drug structures, the preclinical research of each ADC drug has different challenges and difficulties.

Up to now, Medicilon has undertaken more than 100 major IND application biopharmaceutical projects, including monoclonal antibodies, double antibodies, polyclonal antibodies, ADCs, viral vaccines and fusion proteins. As of May 2022, Medicilon has successfully assisted in the clinical approval of 10 ADC drugs and has multiple ADC projects under development.

   ❖  Provides toxin small molecules: DM1, MMAE, Exatecan, Dxd, SN38, etc
   ❖  Provides the targets: Her2, Her3, Trop2, Claudin 18.2, CD33, Muc1, FR, etc
   ❖  Has rich experience in developing and validating analysis methods for different targets, and can effectively analyze the expression level and accessibility of targets according to needs, and provide constructive suggestions for target selection.

Synthesis of ADC Payloads

Medicilon's compound library has a variety of chemical ADC payloads with different mechanisms of action for customers to choose from. At the same time, ADCs can be customized and synthesized according to the specific needs of customers.

   ❖  Tubulin inhibitors
   ❖  DNA damaging agents
   ❖  Immunomodulators

Conjugate Strategies of ADCs

The three main components of ADCs are the antibody, the linker, and the payload.

   ❖  The antibody is responsible for target engagement, it can be in form of Mab, Fab, Bispecific Ab or nanobody. 
   ❖  The linker connects antibody and payload, typically in a form of cleavable or non-cleavable. It is key to ADC stability and responsible when to release the payload. 
   ❖  The payload is a highly potent toxin with defined mode of action. It is responsible for killing cancer cells.

Medicilon Case:

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ADC crosslinking strategy based on cysteine

   ❖  Provide 5mg, 50mg and 500mg scale of ADC crosslinking service, timeline: 2-4weeks.
   ❖  Linker-payload: MC-MMAE, MC-MMAF, MC-GGFG-DX8951, MC-SN38 etc.
   ❖  QC methods including SEC, HIC and LC-MS/MS.
   ❖  DAR evaluation through HPLC and LC-MS/MS.

ADC in Vitro Analysis

With more than 200 cancer cell lines, the Medicilon Biological team has a wide selection of ADC target protein positive and negative tumor cells. In addition, the Medicilon Biological team has extensive experience in cell labeling and FACS-based cell viability analysis to help screen optimal antibodies.

Medicilon Case:

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MV-4-11 cells and PC-3 cells were treated with compound A and stained with PI for FACS-based cell cycle analysis. The data shown that compound A dramatically block the cell cycle of MV-4-11 cells and did not affect PC-3 cells too much.

ADC Pharmacology Evaluation

One important pharmacological parameter of an ADC is the in vivo efficacy that directly reflects its potency and influences clinical trial designs. Our animal models are all established and maintained under the regulation of AAALAC. Pharmacology studies are conducted according to GLP-like standards. At present, more than 300 tumor evaluation models in six categories have been established by Medicilon.

   ❖  Tumor models for multiple tumor diseases 

   ❖  Various laboratory animal Rodents : Mouse/Rat, Rabbit Non- Rodents : Beagle Dog, Mini Pig, Non-human Primate 

   ❖  Diverse selections of model types 

           Xenograft models 
           Syngeneic models 
           Orthotopic xenograft models 
           Transgenic models 
           hPBMC/CD34+ HSC humanized models 
           PDX models

Medicilon Case:

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A humanized anti-EGFR monoclonal antibody (named RC68) was purifed and conjugated with MMAE using a MC-VC-PAB or PY-VC-PAB linker. The in vivo antitumor activity of RC68-MC-VC-PAB-MMAE and RC68- PY-VC-PAB-MMAE were performed by Medicilon.

In vivo antitumor activity of RC68-based ADCs. BALB/c nude mice were implanted subcutaneously with H125 cells and when the solid tumor reached 100–300 mm3, the mice were randomized and treated intravenously with indicated drug weekly. The effect of each treatment on the growth of tumors was measured for tumor volumes and their body weights were measured twice per week. At the end of the experiment, the tumors were dissected and photoimaged.

ADC Pharmacokinetics Study

ADC raises the difficulties of PK study for each component ADC molecules owning unique PK characteristics. Medcilon provides high quality quantification assays for key parameters in ADC PK study, presenting accurate results.

Analyte
Description
Common Analysis Methods
Conjugated AntibodyAntibody with minimum of DAR >= 1LBA
Total AntibodyConjugated, partially unconjugated and fully unconjugated (DAR >= 0)LBA
Small MoleculesReleased/free samllmolecule and its metabolitiesLC-MS/MS
ADAAntibodies against antibody of ADC, linker or drugLBA


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Benchmarking with global lab standard for results with high consistency. Developing stable and reliable methods for results with high correlation.

ADC Immunogenicity

Immunogenicity is a key parameter when evaluating biologic therapeutics. It could increase the risk for adverse effect and reducing ADC efficacy. Medicilon fully understands the compexity of ADA evaluation and offers our clients with comprehensive immunogenicity assays.

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ADC Safety Assessment

Medicilon offers rigorous and specific safety assessment services strictly following S6 & S9 Regulation of ICH and in compliance with the requirement of NMPA, FDA, OECD and TGA.

   ❖  Single dose/Repeat dose toxicity (With TK)
   ❖  Tissue cross-reactivity
   ❖  ADA test.

Contact Us
E-mail:
marketing@medicilon.com
Address:
585 Chuanda Rd, Pudong, Shanghai, China, 201299 (Headquarters)
1 Broadway, 9th Fl, Cambridge Innovation Center, Cambridge, MA 02142, US
Kelvinstraat 41b, 6601 HH Wijchen, The Netherlands
Allia Future Business Centre Kings Hedges Road Cambridge CB4 2HY, UK

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