AAPharmaSyn supports clients in the design and synthesis of:

Antibody-drug conjugates (ADCs) are innovative biopharmaceutical products in which a monoclonal antibody is linked to a small molecule drug with a stable linker. Most of the ADCs developed so far are for treating cancer, but there is enormous potential for using ADCs to treat other diseases. As of 2024, ten ADCs have been approved by the United States Food and Drug Administration(FDA), and more than 90 ADCs are under worldwide clinical development. In cancer application, upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development.

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step diagram

CIRCULATION

ADC solution is prepared and released into bloodstream

Challenge: A stable linker is required to limit non-target toxicity

ADC linker technology largely comprises of:

ADC Linker Technology

Release Mechanism

Designed to be cleaved through disulfide exchange with an intracellular thiol, such as glutathione

Designed for serum stability and degradation in acidic compartments within the cytoplasm

Designed to be enzymatically hydrolyzed by lysosomal proteases such as cathepsin B

Nonreducible and designed for intracellular proteolytic degradation

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chemical

Chemical Structures of non-cleavable and cleavable linkers. (A) SMCC linkers. (B) Maleimidocaproyl linker. (C) Protease cleavable peptide- Based linker. (D)Reducible disulfide linker. (E) Acid-sensitive hydrazone linker.

As of 2021 among the 114 completed or ongoing human trials, there is a lack of diversification in the medicinal payloads utilized, with only 7 payload preparations reported, (4 additional trials are ongoing with non-reported structures). Six of seven payload mixtures are derived from natural product sources, highlighting the value of natural products as cytotoxic payloads for ADC in research studies.

Custom cytotoxic payloads comprise an active area of inquiry.  Please inquire for additional discussion. 

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Trastuzumab emtansine (Kadcyla) for treatment of Her2-positive breast cancer FDA-approved in 2013

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Gemtuzumab ozogamicin (Mylotarg) for treatment of CD33-positive acute myelogenous leukemia FDA-approved in 2000; withdrawn in 2010

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Brentuximab vedotin (adcetris) for treatment of CD30-positive relapsed or refractory Hodgkin's lymphoma FDA-approved in 2011