Each ADC R&D project is its own challenge due to the varieties in the assembly of ADC molecules. With this concept in mind, Medicilon promises careful planning, meticulous execution and accurate results through years of practical experience and effective communication with our clients.
Solutions:- Each ADC R&D project is its own challenge due to the varieties in the assembly of ADC molecules. With this concept in mind, Medicilon promises careful planning, meticulous execution and accurate results through years of practical experience and effective communication with our clients.Up to 2022, 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, etcProvides the targets: Her2, Her3, Trop2, Claudin 18.2, CD33, Muc1, FR, etcHas 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 offers clients with a pool of payload drugs of various mechanisms. We also offer custom synthesis of payload drugs as clients demands.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 inhibitorsDNA damaging agentsImmunomodulatorsProvides 6 payloads of all marketed ADCs Provides 20+ payload derivatives of marketed ADCsProvides independent R&D payloads
Medicilon High Potency Laboratory
- What are the components of antibody-drug conjugates?ADC drugs are composed of three parts: antibody, the linker, and the payload.Antibody:Specific antibodies against tumor antigens, expression is restricted in normal cells.The antibody is responsible for target engagement, it can be in form of Mab, Fab, Bispecific Ab or nanobody.Conjugate (Linker):Conjugate payloads to antibodies. 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.Payload:The payload is a highly potent toxin with defined mode of action. It is responsible for killing cancer cells.
- Medicilon Case:
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:
ADC Binding Assay
A: HER2 ADCs (BB-1701 & DS-8201) were incubated with N87 cells and then analyzed through FACS, MFI of PE on secondary antibodies against ADCs were calculated.B：HER2 protein was immobilized on M5 chip, DS-8201 was serial diluted and injected into the chip, binding affinities of HER2 and DS-8201 was analyzed through Biacore 8K.FACS-based ADC binding assay (Figure A: HER-2 ADC DS-8202, BB-1701 binding with BT-474 cells which is HER2 highly expressing cells).SPR analysis of ADC with antigen in protein level (Figure B: DS-8201 binding with HER2 protein). Provide Kd, Kon, Koff values for binding.Provide other methods for ADC binding, e.g. ELISA and HTRF
ADC Internalization: Confocal Imaging
OVCAR-3 cells were incubated with FITC-labeled ADC for 24 hours, the cells were incubated with Lyso-Tracker and DAPI and then analyzed through con-focal microscope.ADC were labeled with fluorophore（e.g. ADC-FITC, ADC-Cy5).Internalization of ADC-FITC were analyzed through con-focal (co-localization of lyso-tracker with ADC-FITC indicating internalization of ADC).Internalization could also be analyzed through LICOR (In cell Western) and FACS.
Cytotoxicity of Payloads or ADC
Payload, nake antibody and ADC were incubated with target cells, cell viability were analyzed through CCK-8, CTG and MTT.
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.
Apoptosis Analysis
MV-4-11 cells were treated with Compound A and stained with PI/Annexin V for FACS-analysis. The data shown that Compound A promotes the apoptosis of MV-4-11 cells.
Pharmacology Research of ADC- Target antigen binding activityRelated pharmacology of target antigen (e.g.: ADCC，CDC)Mechanism of payloads and metabolites (focus on the difference in pharmacology mechanism ADCs, naked antibodies,payload and metabolites).
Pharmacology Evaluation of ADC- 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.We conduct our tests with GLP-like standards.We have established more than 200 types of oncological models for ADC efficacy assessment.Tumor models for multiple tumor diseasesDiverse selections of model typesXenograft modelsSyngeneic modelsOrthotopic xenograft modelsTransgenic modelshPBMC/CD34+ HSC humanized modelsPDX modelsVarious laboratory animalRodents : Mouse/Rat, RabbitNon- Rodents : Beagle Dog, Mini Pig, Non-human Primate
- Medicilon Case:
In vivo antitumor activity of RC68-based ADCs.
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.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 by monitoring 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.
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.
ADC Safety assessmentMedicilon 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.
Service Cases
Medicilon assisted Bio-Thera's bispecific neutralizing antibody drug for injection BAT2022 for the treatment of new coronary pneumonia was approved for clinical use
The first China-made targeting folic acid receptor FRα ADC injection BAT8006 was approved for clinical use
Medicilon Assisted DAC Biotechnology's Fourth ADC Drug DXC007 Getting Approved for Clinical Use
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