Immunoconjugates – complex molecules that combine a targeting component, a linker molecule and a therapeutic or diagnostic component (also known as a payload) – have been described as magic bullets as they allow the precise delivery of an active molecule to its target. [1]
In the early 1900s, Paul Erlich of the Institute of Experimental Therapy (Institut für experimentelle Therapie) was concerned about the off-target effects seen with the systemic treatment of bacterial infections. He came up with the idea of a ‘magic bullet’ (Zauberkugel); a molecule that could target specific microbes without harming the body itself. The first drug to fit the description of a magic bullet was Erlich’s arsphenamine (Salvarsan), an antimicrobial for treating syphilis that specifically killed the spirochete Treponema pallidum. Salvarsan was launched in 1910 and used until the 1940s when it was supplanted by penicillin. [2, 3]
Throughout the 20th century, the idea that there could really be a magic bullet – a systemically delivered treatment that targeted disease without harming healthy tissue – became a goal for drug developers. This took a major step forward with the 1986 launch of the first monoclonal antibody drug, Orthoclone OKT3 (muromonab-CD3), for the prevention of kidney transplant rejection. [4]
Almost a hundred years after Erlich first used the term, Pfizer/Wyeth's gemtuzumab ozogamicin (Mylotarg) was approved by the FDA (Food & Drug Administration) for the treatment of acute myeloid leukaemia (AML). [5] Using a monoclonal antibody to deliver a drug payload, the immunoconjugate Mylotarg took the concept to a new level – a magic bullet that is closer to a biological missile. [6]
Mylotarg only made sales of $8.8 million in its first quarter, but the market is now huge. In 2023, the global antibody drug conjugates market was worth around $9.7 billion, with potential to grow to $19.8 billion by 2028, growing at a CAGR (compound annual growth rate) of 15.2% from 2023 to 2028. [7, 8]
Finding the target
The ideal target for an immunoconjugate should not be secreted into the circulation, should be highly expressed at the site where the drug is to act, and be expressed only at low levels or absent in other tissues. The targeting molecule, usually an antibody or antibody fragment, is responsible for directing the immunoconjugate to its site of action. The ideal targeting molecule should have high levels of affinity and selectivity for the target, with little or no off-site binding. It should also have a long plasma half-life and have low propensity for immunogenicity. [6, 9]
Selecting the payload
The choice of active molecules used in immunoconjugates will depend on the indication, and include: [6, 9]
● Drugs, including cytotoxics, cytokines and oligonucleotides
● Radioisotopes (for imaging and therapy)
● Imaging labels
Making the connection: Linker molecules
The linker molecule connects the active ingredient and the targeting molecule. It needs to be sufficiently stable in plasma to ensure that the active ingredient reaches its target, and then release it at the right location and time through enzymatic cleavage or chemical degradation. Linkers can be cleavable or non-cleavable, and the choice depends on the environment where the drug is to be released. Examples of cleavable linkers include acid-sensitive, reductive and enzyme-cleavable linkers. Non-cleavable linkers are used when the targeting molecule is broken up by lysosomes after being internalised into the target cell. The linker should not induce immunoconjugate aggregation. [6, 9]
The challenges for immunoconjugates
Immunoconjugates can be associated with a range of side effects. Most of these relate to the side effects associated with the payload, for example the expected adverse effects seen with cancer chemotherapeutics. If the antibody engages with targets on healthy cells, payload accumulation at these sites can cause adverse effects. There can also be problems if the linker releases the payload too soon, away from the target. These effects can be mitigated by adjusting the immunoco...
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