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ADC Linkers

Antibody-drug conjugates (ADCs), consisting of monoclonal antibodies (mAb), cytotoxic payloads and linkers, have evolved rapidly in recent years and are progressively revolutionizing clinical cancer therapy. To fight cancer, the antibodies attach to proteins on the surface of tumor cells. Once the ADC is there, the tumor cells engulf the ADC; rip apart the linker through chemical, enzymatic or biological processes; and release a small molecule payload. The payload then kills the tumor cells. These therapies are envisioned to act like guided missiles, delivering a killing drug specifically to cancer cells without harming healthy cells. Currently, dozens of ADCs have been approved and over hundreds are in various stages of clinical trials.

The linker connects antibody to cytotoxic payload and is a key component of ADC. Linkers provide ADC with the following characteristics. (1) high stability in the circulation, and (2) specific release of the payload in the target tissue. To meet these requirements, various linkers have been developed and can be classified into two types based on their cleavage method - cleavable and noncleavable linker. Cleavable linker has a chemical trigger in its structure that can be efficiently cleaved to release cytotoxic payload in the tumor. More than 80% of clinically approved ADCs employ cleavable linkers. For example, Trodelvy is an anti-TROP-2 mAb conjugated to SN-38 via a cleavable maleimide linker (acidity) with a short pegylated unit.  In contrast to cleavable linkers, there is no chemical trigger in the structure of the noncleavable linker, and it is part of the payload. Most of the non-cleavable linkers are based on maleimidocaproyl  (MC) and 4-maleimidomethyl cyclohexane-1-carboxylate (MCC). Recently, researchers have been developing hydrophilic non-cleavable linkers containing PEG with alkynes and piperazines. However, this new technology has not yet reached clinical maturity. 

Trodelvy-formula-ADC

The use of PEGs as a linker between the antibody and payload molecules allows for higher ADC loading. PEGs create a protective shield that wraps the ADC payload from its microenvironment, improving solubility and stability. Other benefits include reduced aggregation and thus lower immunogenicity, improved pharmacokinetics, increased circulation time and reduced toxicity. Biopharma PEG offers a variety of PEG linkers to facilitate antibody-drug conjugate (ADC) development projects. All PEG linkers are of >95% purity and they are the basic building blocks for a successful ADC.

Technique support: GMP standard production support, impurity control. Contact for Technical Files.

References:
​1. Zheng Su, Dian Xiao, Fei Xie, Lianqi Liu, Yanming Wang, Shiyong Fan, Xinbo Zhou, Song Li, Antibody–drug conjugates: Recent advances in linker chemistry, Acta Pharmaceutica Sinica B, Volume 11, Issue 12, 2021,Pages 3889-3907, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2021.03.042.
2. Joubert, N.; Beck, A.; Dumontet, C.; Denevault-Sabourin, C. Antibody–Drug Conjugates: The Last Decade. Pharmaceuticals 2020, 13, 245. https://doi.org/10.3390/ph13090245

Catalog No. Name Structure M.W. Purity
MF001024 mPEG-SCM mPEG-SCM ≥95%
HO017017 COOH-PEG-COOH COOH-PEG-COOH ≥95%
HE002005 OH-PEG-NH2 OH-PEG-NH2 ≥95%
HE002016 OH-PEG-PA OH-PEG-PA ≥95%
MD002002 OH-PEG8-OH OH-PEG8-OH 370.436 ≥95%
MD002002 OH-PEG9-OH OH-PEG9-OH 414.488 ≥95%
MD005002 NH2-PEG4-OH NH2-PEG4-OH 193.2 ≥95%
MD005002 NH2-PEG12-OH NH2-PEG12-OH 545.667 ≥95%
MD005016 NH2-PEG4-COOH NH2-PEG4-COOH 265.3 ≥95%
MD005016 NH2-PEG24-COOH NH2-PEG24-COOH 1146 ≥95%
MD001005 mPEG3-NH2 mPEG3-NH2 163.2 ≥95%
MD001005 mPEG36-NH2 mPEG36-NH2 1616.95 ≥95%