{"id":27933,"date":"2025-04-28T10:00:00","date_gmt":"2025-04-28T08:00:00","guid":{"rendered":"https:\/\/mabdesign.fr\/?p=27933"},"modified":"2025-07-28T15:53:24","modified_gmt":"2025-07-28T13:53:24","slug":"adcs-antibodies-and-cytotoxic-molecules-united-against-tumours","status":"publish","type":"post","link":"https:\/\/mabdesign.fr\/en\/adcs-antibodies-and-cytotoxic-molecules-united-against-tumours\/","title":{"rendered":"ADCs : antibodies and cytotoxic molecules united against tumours"},"content":{"rendered":"\t\t
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From Paul Ehrlich\u2019s early \u201cmagic bullet\u201d concept to today\u2019s approved therapeutics, Antibody-Drug Conjugates (ADCs) represent a major breakthrough in targeted cancer therapy. By combining the selectivity of monoclonal antibodies with the potency of cytotoxic agents, ADCs aim to eliminate tumor cells while sparing healthy tissues. This article dives into the evolution, design strategies, and key challenges of these complex biologics.\u00a0<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t

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Historical background of ADCs<\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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The history of Antibody-Drug Conjugates (ADCs), revolutionary biomedicines in oncology, goes back to the visionary work of Paul Ehrlich<\/strong>, a German scientist at the beginning of the 20th century. Paul Ehrlich is often regarded as the father of modern immunology<\/strong> and chemotherapy. His concept of the \u2018magic bullet\u2019<\/strong> laid the foundations for targeted therapy, an idea that resonates particularly well with ADCs.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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Figure 1<\/strong>: Major scientific breakthroughs that paved the way for the development of ADCs, adapted from Zhiwen Fu, <\/span>Shijun<\/span> Li, <\/span>Sifei<\/span> Han, Chen Shi & Yu Zhang, <\/span><\/span>Signal Transduction and Targeted Therapy<\/span><\/span>, 2022.<\/span><\/span><\/em><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t

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Paul Ehrlich –\u00a0(1854-1915)<\/em><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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At the beginning of the 1900s, Ehrlich was working on ways to treat infections and diseases without damaging healthy tissues. He proposed the idea of a “magic bullet” \u2014\u00a0<\/span><\/span>a compound capable of specifically targeting pathogens or diseased cells<\/span><\/span><\/strong> (such as cancer cells) while sparing healthy tissues. At the time, there was no advanced technology to bring this idea to <\/span>reality<\/span>, <\/span><\/span>but his vision <\/strong><\/span>remained<\/span> a major source of inspiration in the development of modern <\/span>medicine<\/span><\/strong><\/span>. Ehrlich<\/span> also <\/span><\/span>made crucial discoveries in the field of antibodies<\/strong><\/span><\/span>\u2014proteins capable of specifically recognizing antigens carried by pathogens such as bacteria and viruses. He suggested that <\/span><\/span>antibodies could be used to deliver therapeutic agents<\/span><\/span><\/strong> directly to specific targets within the body, a <\/span><\/span>concept that foreshadowed the mechanism of action of ADCs<\/span><\/span><\/strong>.<\/span> It was only several decades after Ehrlich\u2019s visionary proposals that <\/span><\/span>advances in immunology and biotechnology<\/span><\/span><\/strong> enabled the conjugation of antibodies to cytotoxic agents.<\/span><\/span>\u00a0<\/span><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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In the 1980s, the first clinical trials involving ADCs were initiated (for example, targeting CD33 in acute myeloid leukaemia), but it was not until the 2000s that the first ADCs were approved by regulatory agencies<\/strong>\u2014such as gemtuzumab ozogamicin, indicated for the treatment of acute myeloid leukaemia<\/strong>. Since the beginning of the 21st century, ADCs have become essential tools in the fight against cancer. Researchers continue to refine ADC design to enhance specificity (and therefore reduce toxicity) and improve therapeutic efficacy.<\/strong> Paul Ehrlich\u2019s idea has thus become a reality\u2014more than a century after his initial intuitions.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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The first ADC trials began in the 1980s, but it was not until the 2000s that the first ADCs were approved<\/strong> by drug regulatory agencies, such as gemtuzumab ozogamicin indicated for acute myeloid leukaemia. Since the beginning of the 21st century, ADCs have become essential tools in the fight against cancer. Researchers continue to refine the design of ADCs to make them more specific and more effective.<\/p>

Paul Ehrlich’s idea has thus become a reality, more than a century after his first intuitions.<\/strong><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t

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Structure and mechanism of action of ADCs <\/h2>\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t
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An Antibody-Drug Conjugate (ADC) is a targeted therapy that harnesses the specificity of a monoclonal antibody for an antigen preferentially expressed on <\/span>tumour<\/span> cells. This biopharmaceutical enables the selective delivery of a highly potent cytotoxic agent directly to cancer cells.<\/span><\/span>\u00a0<\/span><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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Figure 2<\/strong>: Structure of an ADC, adapted from <\/span>Dumontet<\/span> C, Reichert J, Senter P, Lambert J, Beck A. <\/span><\/span>Nature Reviews Drug Discovery<\/span><\/span>, 2023.<\/span><\/span><\/em><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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An ADC is a <\/span>\u201c<\/span><\/b>prodrug\u201d<\/span><\/i><\/b>,<\/span><\/b> meaning it is <\/span>administered in an inactive form<\/span><\/b> and subsequently metabolized to produce <\/span>an active metabolite<\/span><\/b>\u2014that is, the <\/span>pharmacologically active form of the ADC<\/span><\/b>. This property helps <\/span>reduce systemic toxicity to healthy cells,<\/span><\/b> in contrast to traditional chemotherapies.<\/span>\u00a0<\/span><\/p>

First, the <\/span>antigen targeted by the ADC<\/span><\/b> must be <\/span>well characterized<\/span><\/b>, <\/span>with high and homogeneous expression on tumour cells and low expression on healthy tissues.<\/span><\/b> Interestingly, complete homogeneity of antigen expression is not absolutely required if compensatory mechanisms such as the bystander effect (see box below) are present. However, antigen homogeneity remains an important criterion in the selection and optimization of ADC candidates.<\/span>\u00a0<\/span><\/p>

Multiple ADCs can be approved for the same cellular target, such as the HER2 antigen (with four approved ADCs), underscoring the challenge of identifying novel therapeutic targets for innovative ADC development.<\/span>\u00a0<\/span><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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An ADC is a <\/span>\u201c<\/span><\/b>prodrug\u201d<\/span><\/i><\/b>,<\/span><\/b> meaning it is <\/span>administered in an inactive form<\/span><\/b> and subsequently metabolized to produce <\/span>an active metabolite<\/span><\/b>\u2014that is, the <\/span>pharmacologically active form of the ADC<\/span><\/b>. This property helps <\/span>reduce systemic toxicity to healthy cells,<\/span><\/b> in contrast to traditional chemotherapies.<\/span>\u00a0<\/span><\/p>

First, the <\/span>antigen targeted by the ADC<\/span><\/b> must be <\/span>well characterized<\/span><\/b>, <\/span>with high and homogeneous expression on tumour cells and low expression on healthy tissues.<\/span><\/b> Interestingly, complete homogeneity of antigen expression is not absolutely required if compensatory mechanisms such as the bystander effect (see box below) are present. However, antigen homogeneity remains an important criterion in the selection and optimization of ADC candidates.<\/span>\u00a0<\/span><\/p>

Multiple ADCs can be approved for the same cellular target, such as the HER2 antigen (with four approved ADCs), underscoring the challenge of identifying novel therapeutic targets for innovative ADC development.<\/span>\u00a0<\/span><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t

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The structure of an ADC consists of three main components:<\/span>\u00a0<\/span><\/p>