ADC Development and Production

ADC OverviewAntibody DevelopmentLinker & Toxin DevelopmentConjugation ProcessQuality ControlContact Us

ADCs represent an innovative cancer treatment that combines the targeting precision of antibodies with the killing power of cytotoxic drugs. Since the first ADC approval in 2000, the technology has evolved through three generations, progressing from random to site-specific conjugation, significantly improving drug stability and therapeutic efficacy.

What are ADCs?

Figure 1: The core components including target antigen, antibody, linker, cytotoxic drug along with their key functions demonstrated. Figure 1. The structure and characteristics of an ADC drug. (Fu Z, et al., 2022)

Antibody

Monoclonal antibodies targeting tumor surface antigens (e.g., HER2, TROP2)

Linker

Available in cleavable (acid-sensitive, enzyme-sensitive) and non-cleavable forms, controlling payload release

Cytotoxic Payload

Including microtubule inhibitors (MMAE) and DNA-damaging agents (SN-38) for tumor cell elimination

Figure 2: ADCs bind to a cancer-specific cell-surface antigen, are internalized into the tumor cell, and release cytotoxin upon degradation to induce cancer cell apoptosis. Figure 2. Mechanism of action of ADCs. (Sheyi R, et al., 2022)

ADCs act like a shuttle, specifically recognizing and binding to well-expressed antigens on tumor cells, delivering cytotoxic drugs via receptor-mediated endocytosis, and releasing toxins in lysosomes to induce apoptosis or cell death through various pathways.

Currently, over 16 ADC drugs are marketed globally, treating various cancers including breast cancer, lymphoma, and lung cancer. More than 200 ADC candidates are in clinical development, expanding beyond traditional targets to emerging antigens (like B7-H3, CLDN18.2) and exploring combination therapies with PD-1 inhibitors.

Table 1. List of Approved ADCs

Brand Name	Company/Companies	Approval Date(s)
Mylotarg	Pfizer	May 2000 (FDA); withdrawn in 2010; re-approved in September 2017
Adcetris	Seagen/Takeda	August 2011 (FDA)
Kadcyla	Roche/ImmunoGen	February 2013 (FDA)
Besponsa	Pfizer	June 2017 (EMA)
Lumoxiti	AstraZeneca	September 2018 (FDA); withdrawn from U.S. market in 2023
Polivy	Roche	June 2019 (FDA)
Padcev	Astellas/Seagen	December 2019 (FDA)
Enhertu	Daiichi Sankyo/AstraZeneca	December 2019 (FDA)
Trodelvy	Immunomedics	April 2020 (FDA)
Blenrep	GlaxoSmithKline	August 2020 (FDA); withdrawn from U.S. market in 2022
Akalux	Rakuten Medical	September 2020 (PMDA, Japan)
Zynlonta	ADC Therapeutics	April 2021 (FDA)
Aidixi	RemeGen	June 2021 (NMPA, China)
Tivdak	Seagen/Genmab	September 2021 (FDA)
Elahere	ImmunoGen	November 2022 (FDA)
RC48	Kelun-Biotech	November 2024 (NMPA, China)

ADCs offer precise targeting, high therapeutic index, and the ability to overcome traditional chemotherapy resistance. However, their complex hybrid structure combining large and small molecules presents significant production, analysis, design, and manufacturing challenges. The production process involves antibody preparation, linker synthesis, small molecule drug preparation, ADC conjugation, purification, and final product manufacturing.

Creative Biogene ADC Development and Manufacturing Services

Creative Biogene delivers a comprehensive solution from antibody discovery and linker design to toxin screening and conjugation optimization. Our platform integrates antibody engineering, chemical synthesis, and bioconjugation for smooth transitions from target validation to commercial production.

Antibody Development and Engineering

High-Affinity Antibody Development: Advanced phage display and single B-cell sorting technologies to construct antibody libraries up to 10⁸. Develop fully human or chimeric antibodies targeting tumor antigens (e.g., HER2, TROP2, CLDN18.2).
CHO Cell Expression System: High-yield monoclonal antibody production using the CHO system for stable cell line construction, antibody humanization, and affinity optimization.
cGMP Antibody Production: Full-service antibody production with purity >95%, endotoxin levels<1.0 EU/µg, and compliance with FDA/EMA regulations.
Affinity Optimization: Directed evolution techniques (e.g., error-prone PCR, yeast display) to enhance affinity to pM levels, ensuring efficient target binding.
Conjugation Site Engineering: Optimizing conjugation sites using site-specific mutations (e.g., Cys-114/Cys-200), ensuring a consistent drug-antibody ratio (DAR) of 3.8±0.2.

Linker and Toxin Development

Linker Design and Validation

1. Cleavable Linkers: Development of cleavable linkers (e.g., Val-Cit-PABC, pH-sensitive sulfonates) with >90% release efficiency in tumor microenvironment (pH 5.5).

2. Non-Cleavable Linkers: Use stable linkers (e.g., thioether) to ensure conjugate stability, with batch-to-batch variation<5%.

Toxin Library and Custom Development

1. Microtubule Inhibitors: High-purity MMAE/MMAF with >98% purity and PEGylation to optimize pharmacokinetics.

2. DNA-Damaging Agents: Example: Camptothecin derivatives with IC50 ≤ 0.1 nM to treat solid tumors and hematologic malignancies.

Conjugation Process Development and Scale-Up

Directed Conjugation

Using cysteine or lysine-directed conjugation ensures uniform DAR.

Thiol-Directed Conjugation

Utilizing maleimide chemistry for precise DAR control, with error margins within ±0.2.

Enzyme-Catalyzed Conjugation

Using microbial transglutaminase (mTGase) for site-specific conjugation, avoiding organic solvent residues (≤10 ppm).

Global Compliant Production Facilities

Equipped with a 2000L single-use bioreactor, capable of meeting clinical and commercial production needs.
Cleanroom meets ISO 14644 Class 5 standards, with a sterile filling capacity of ≥200 bottles/min.
Supporting multi-center clinical trials in the US, and Europe.

Supply Chain and Raw Material Assurance

Mammalian Cell Culture (CHO-S and HEK293): Antibody yield ≥5 g/L using Fed-batch processes.
Microbial Expression Systems (E. coli): Single-chain antibody (scFv) production with a 4-week turnaround time.

Quality Control and Analytical Methods

Test Item	Analysis Method
DAR Measurement	Hydrophobic Interaction Chromatography (HIC-HPLC)
Free Toxin Residue	LC-MS/MS
Aggregation Analysis	SEC-MALS (Wyatt Technology)
Potency Testing	Cytotoxicity Assay (MTT Method)

Service Flow and Delivery Standards

Stage	Key Deliverables	Timeline
Process Development	Process development report (including DoE data)	14-20 weeks
Toxicology Batch Production	Toxicology study samples (5-10 kg)	12-15 weeks
GMP Clinical Production	Clinical batch (COA + batch records)	Custom
Commercial Supply	PPQ report + stability data package	Custom

Contact Us

With over 10 years of experience in antibody engineering and conjugation processes, Creative Biogene serves over 100 international pharmaceutical companies, mastering over 80% of market-relevant target technologies. Our complete supply chain and critical raw material inventory ensure seamless production. We strictly adhere to USP<129>and ICH Q2(R2) standards, providing robust compliance assurance. Contact Creative Biogene to elevate your innovative drug development to new heights!

References:

Sheyi R, de la Torre BG, Albericio F. Linkers: An Assurance for Controlled Delivery of Antibody-Drug Conjugate. Pharmaceutics. 2022;14(2):396. Published 2022 Feb 11.
Fu Z, Li S, Han S, et al. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93. Published 2022 Mar 22.

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