抗体药物结合物：“神奇子弹”成为现实

Antibody-drug Conjugates:‘Magic B u llets’ B ecome R eality Cancer therapy goes monoclonal Cancer is one of the leading causes of deathglobally, with a projected 16.3 million deaths by2040.1Interventions for the treatment of cancerinclude surgical resection, radiotherapy, anddrug therapy. While effective, the longstandinguse of cytotoxic chemotherapy was a precariousbalancing act of achieving sufficient antitumorefficacy while minimizing damage to healthycells and debilitating side effects. Consequently,the 1990s saw a move away from traditionalchemotherapy towards more targeted approaches, with tumor-specific antigensemerging as unique druggable targets. Targetedbiologics such as monoclonal antibodies (mAbs)provided versatile new drug platforms, and in1997 rituximab became the first mAb approvedfor cancer in the treatment-resistant B celllymphoma setting. An explosion in mAb-drivencancer drug development followed, with 141mAbs currently marketed for the treatment ofvarious forms of cancer (Figure 1). Cancer therapy then was evolving from potentbut somewhat indiscriminate chemotherapyto targeted biological therapy. Proposed byGerman physician Paul Ehrlich in 1907, theideal would be a hybrid encompassing thecytotoxicity of chemotherapy with the tumorspecificity of a biologic. Early development ofchemotherapy had already yielded an array of cellular toxins too potent to administersystemically, but which could now potentiallybe linked to an antibody to become a formof “smart chemotherapy.” These antibody-drug conjugates (ADCs) thus had thepotential to make Ehrlich’s “magic bullet”theory the new tool in the fight againstcancer.2 Antibody-drug Conjugates:‘Magic B u llets’ B ecome R eality The makeup of ADCs The second component is the linker molecule.This links the antibody and payload moieties,and functions to ensure that the highly cytotoxicpayload remains stably bound to the antibodyand thus inert while in the systemic circulation.Cleavable linkers, most commonly used indevelopment to date, are such that allow releaseof the payload in response to intracellular orextracellular environmental differences, suchas changes in pH or redox potential, whichcause a bond cleavage.3Conversely, non-cleavable linkers release the attached payloadupon lysosomal degradation of the antibody.These bonds ensure greater stability in thecirculation and tumor microenvironment and areassociated with improved efficacy and reducedtoxicity over cleavable linkers. As exemplified by ADCs consist of three components: an antibody,a linker, and a payload. An antibody againsta tumor antigen acts as a targeted deliverysystem, guiding the ADC directly towardsantigen-expressing tumor cells, avoiding toxicityto healthy cells and unwanted side effects.Target selection is crucial to the effectivenessof ADCs, and those preferentially or exclusivelyexpressed at high levels on the surface of tumorcells make the best targets. In terms of antibodyselection, current ADCs are widely based onimmunoglobulin G (IgG) which combines a longhalf-life with strong antibody-mediated immuneeffects. Elsewhere, the problem of potentialimmunogenic side effects has been addressedthrough the use of chimeric and humanizedantibodies. Antibody-drug Conjugates:‘Magic B u llets’ B ecome R eality trastuzumab emtansine (Kadcyla), developed byRoche, composed of trastuzumab conjugatedto a DM1 molecule via a non-reducible thioetherlinker,4which demonstrated greater activitywhen compared to conventional unconjugatedtrastuzumab and to trastuzumab conjugatedvia reducible disulfide linkers to othermaytansinoids.5 carried by the ADC construct. Currently, the most used payloads in ADCdevelopment are auristatins, specificallymonomethyl auristatin E (MMAE) andmonomethyl auristatin F (MMAF), with 70 ADCsin active development as shown in Figure 2. Asignificant disparity between the most adoptedand alternative payloads is observed, whichcan be attributed to the factors of payloadproperties, such as the stability and toxicity,that present challenges in clinical applications. The final and most important component ofan ADC is the payload, the cytotoxic moleculeresponsible for its cancer-killing effect. Whileearly ADCs utilized traditional chemotherapeuticagents as a cytotoxic payload, these lackedefficacy as such agents were not potentenough to produce sufficient anticancer effect.4However, structural conformation of an antibodyalso limits the amount of payload that can be Accordingly, an ideal payload should becytotoxic enough to achieve a therapeutic effectwhile reducing the requirement for higher dosesthat lead to harmful side effects.6 Antibody-drug Conjugates:‘Magic B u llets’ B ecome R eality Mechanisms of ADCs ADCs are administered intravenously intothe bloodstream to avoid degradation of themAb component. The attached antibody actsas a “biological missile,” guiding the ADC tothe antigen expressing tumor cells where itbinds, forming an ADC-antigen complex that issubse