Pathophysiologic and Pharmacologic Considerations to Improve the Design and Application of Antibody–Drug Conjugates

Abstract

Antibody-drug conjugates (ADC) have emerged as one of the pillars of clinical disease management in oncology. The biggest hurdle to widespread development and application of ADCs has been a narrow therapeutic index. Advances in antibody technologies and formats as well as novel linker and payload chemistries have begun to facilitate structural improvements to ADCs. However, the interplay of structural characteristics with physiologic and pharmacologic factors determining therapeutic success has garnered less attention. This review elaborates on the pharmacology of ADCs, the pathophysiology of cancerous tissues, and the reciprocal consequences on ADC properties and functions. While most currently approved ADCs utilize either microtubule inhibition or DNA damage as primary mechanisms of action, we present arguments to expand this repertoire and highlight the need for payload mechanisms that exploit disease-specific vulnerabilities. We promote the idea that the choice of antibody format, targeting antigen, linker properties, and payload of an ADC should be deliberately fit for purpose by taking the pathophysiology of disease and the specific pharmacology of the drug entity into account, thus allowing a higher probability of clinical success.

Uncovering therapeutic opportunities in the clinical development of antibody‐drug conjugates

“…9 The successful development of ADCs depends on the correct use of the combination of three structural components, including the design of the antibody against a specific tumour target, the use of a suitable linker, and the selection of an appropriate payload (the cytotoxic component of ADC). 7,[10][11] Regarding the selection of a specific monoclonal antibody, beyond the concrete designing of the antibody itself or the use of specific formats and structures, the identification of a target only expressed within the tumour is key to demonstrating activity with reduced on-target and off-tumour toxicity. In this context, the best-case scenario will be the use of an antibody against a tumour-associated target (TAT) only expressed in the tumour where the selected payload demonstrated the highest antitumoral activity.…”

“…In this context, the best-case scenario will be the use of an antibody against a tumour-associated target (TAT) only expressed in the tumour where the selected payload demonstrated the highest antitumoral activity. 7 Approved ADCs have demonstrated significant clinical efficacy in increasing time-to-event endpoints, like progression-free survival (PFS) or overall survival (OS) in particular indications, where there is a clear presence of the TAT, as is the case for those targeting HER2 like trastuzumab emtansine and trastuzumab deruxtecan. [12][13][14] However, a deep evaluation of target expression among all tumour types with the aim of identifying potential clinical options for development has not been performed.…”

“…1,4,5 The use of monoclonal antibodies to guide the delivery of active but toxic compounds have demonstrated to be beneficial for patients, with the first approval of antibody-drug conjugates (ADCs) developed for lymphoma and breast tumours. 6,7 At this moment, there are 11 ADCs approved 8 and many others in clinical development. 9 The successful development of ADCs depends on the correct use of the combination of three structural components, including the design of the antibody against a specific tumour target, the use of a suitable linker, and the selection of an appropriate payload (the cytotoxic component of ADC).…”

“…Regarding the selection of a specific monoclonal antibody, beyond the concrete designing of the antibody itself or the use of specific formats and structures, the identification of a target only expressed within the tumour is key to demonstrating activity with reduced on‐target and off‐tumour toxicity. In this context, the best‐case scenario will be the use of an antibody against a tumour‐associated target (TAT) only expressed in the tumour where the selected payload demonstrated the highest antitumoral activity 7 …”

Antibody-Drug Conjugates Containing Payloads from Marine Origin

“…Given the biological relevance and structural complexity of these classes of cancer therapeutics, many reviews have been devoted to all aspects of the ADCs, including general details [ 20 , 21 , 24 , 25 , 26 , 28 , 29 , 34 , 35 , 36 , 37 , 38 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ], the role of the linker [ 30 , 32 , 33 ] as well as the clinical status of ADCs [ 56 , 57 , 58 , 59 ]. As described in the Introduction, ADCs rely on several fields: the antibody belongs to biology and biochemistry, while the linker and payload fall into organic chemistry.…”