Pan-cancer analysis of antibody-drug conjugate targets and putative predictors of treatment response.

BACKGROUND

Antibody-drug conjugates (ADCs) are a rapidly expanding class of compounds in oncology. Our goal was to assess the expression of ADC targets and potential downstream determining factors of activity across pan-cancer and normal tissues.

MATERIALS AND METHODS

ADCs in clinical trials (n = 121) were identified through ClinicalTrials.gov, corresponding to 54 targets. Genes potentially implicated in treatment response were identified in the literature. Gene expression from The Cancer Genome Atlas (9000+ cancers of 31 cancer types), the Genotype-Tissue Expression database (n = 19,000 samples from 31 normal tissue types), and the TNMplot.com (n = 12,494 unmatched primary and metastatic samples) were used in this analysis. To compare relative expression across and within tumour types we used pooled normal tissues as reference.

RESULTS

For most ADC targets, mRNA levels correlated with protein expression. Pan-cancer target expression distributions identified appealing cancer types for each ADC development. Co-expression of multiple targets was common and suggested opportunities for ADC combinations. Expression levels of genes potentially implicated in ADC response downstream of the target might provide additional information (e.g. TOP1 was highly expressed in many tumour types, including breast and lung cancers). Metastatic compared to primary tissues overexpressed some ADCs targets. Single sample "targetgram" plots were generated to visualise the expression of potentially competing ADC targets and resistance/sensitivity markers highlighting high inter-patient heterogeneity. Off-cancer target expression only partially explains adverse events, while expression of determinants of payload activity explained more of the observed toxicities.

CONCLUSION

Our findings draw attention to new therapeutic opportunities for ADCs that can be tested in the clinic and our web platform (https://tnmplot.com) can assist in prioritising upcoming ADC targets for clinical development.

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.B.: Financial interests: personal consulting fees from Kardo srl (personal); travel support for attending meetings from Daiichi-Sankyo and Lilly. G.N.: Travel support for attending meetings from Lilly and Sanofi. M.M.: Travel support for attending meetings from Lilly. L.L.: Financial interests: Consulting fees from Exact Sciences, Helsinn, EISAI; honoraria for speakers’ bureaus from Gilead, Exact Sciences, Helsinn; support for attending meetings from Lilly and Gilead; advisory board for Lilly, Exact Sciences, AstraZeneca, Italfarmaco, Accord, Seagen and Daiichi Sankyo (all personal and financial). G.V.: Financial interests: Advisory board for Gilead; speakers’ bureaus: Novartis, Lilly; support for attending meetings: Pfizer, Lilly (all personal and financial). B.P.: Financial interests: Consulting fees from AstraZeneca (institutional), Seagen (institutional), Gilead (institutional), Novartis (institutional), Lilly (institutional), MSD (institutional), Pierre Fabre (personal), Daiichi-Sankyo (institutional/personal); research funding (to the institution): Astra Zeneca, Daiichi-Sankyo, Gilead, Seagen, MSD; travel support: Astra Zeneca; Pierre Fabre; MSD; Daiichi-Sankyo, Pfizer. F.A.: Financial interests: grants or speaker/Advisory compensated to hospital: AstraZeneca, Daiichi Sankyo, Pfizer, Lilly, Relay; honorarium: Lilly. M.P.: Financial interests: Travel support for attending meetings from Gilead and Novartis. C.C.: Financial interests: Personal fees for consulting, advisory role, and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead, Daiichi Sankyo, AstraZeneca, and Pfizer. L.P.: Financial interests: Consulting fees and honoraria for advisory board participation from Pfizer, Astra Zeneca, Merck, Novartis, Bristol-Myers Squibb, Stemline-Menarini, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, Exact Sciences (personal), and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer and Bristol Myers Squibb. G.C.: Financial Interests: AstraZeneca, Invited Speaker, Personal; AstraZeneca, Advisory Board, Personal, BMS, Advisory Board, Personal; Celcuity, Advisory Board, Personal; Daiichi Sankyo, Invited Speaker, personal; Daiichi Sankyo, Advisory Board, Personal; Exact Sciences, Advisory Board, Personal; Gilead, Advisory Board, Personal, Advisory Board; Lilly, Advisory Board, Personal; Menarini, Advisory Board, Personal, Advisory Board; Merck, Advisory Board, Personal; Novartis, Invited Speaker, Personal; Pfizer, Writing Engagement, Personal; Pfizer, Advisory Board, Personal; Pfizer, Invited Speaker, Personal; Roche, Advisory Board, Personal; Roche, Invited Speaker, Personal; Veracyte, Advisory Board, Personal; Ellipsis, Other, Personal, Advisory Board; Astellas, Funding, Institutional, Financial interest, Phase I studies; AstraZeneca, Funding, Institutional, Financial interest, Phase I studies; Blueprint Medicine, Funding, Institutional, Financial interest, Phase I studies; BMS, Funding, Institutional, Financial interest, Phase I studies; Daiichi Sankyo, Funding, Institutional, Financial interest, Phase I studies; Kymab, Funding, Institutional, Financial interest, Phase I studies; Merck, Research Grant, Institutional, Financial interest, Investigator Initiated Trial; Novartis, Funding, Institutional, Financial interest, Phase I studies; Philogen, Funding, Institutional, Financial interest, Phase I studies; Relay Therapeutics, Coordinating PI, Institutional, Financial interest, Phase I clinical basket trial; Roche, Funding, Institutional, Financial interest, Phase I studies; Sanofi, Funding, Institutional, Financial interest, Phase I studies. Non-financial interests: Consiglio Superiore di Sanità, Officer, Italian National Health Council as Advisor for Ministry of Health; ESMO, Officer, ESMO Clinical Practice Guidelines Chair; ESMO, Member of Board of Directors, Chair of Clinical Practice Guidelines Committee; Europa Donna, Advisory Role, Member of the Scientific Council. Patient advocacy association; EUSOMA, Officer, Member of the Advisory Council; Fondazione Beretta, Advisory Role, Cancer Research Foundation; Lega Italiana Lotta ai Tumori, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention. G.B.: Financial Interests: AstraZeneca, Advisory Board, Personal; AstraZeneca, Other, Personal, Consultancy; Daiichi Sankyo, Advisory Board, Personal; Daiichi Sankyo, Other, Personal, Consultancy; Lilly, Advisory Board, Personal; Lilly, Invited Speaker, Personal; Novartis, Advisory Board, Personal; Pfizer, Advisory Board, Personal; Roche, Other, Personal, Consultancy; MSD, Other, Personal, Consultancy; Gilead, Other, Personal, Consultancy; Sanofi, Other, Personal, Consultancy; Roche, Invited Speaker, Personal; AstraZeneca, Invited Speaker, Personal; Daiichi Sankyo, Invited Speaker, Personal; MSD, Invited Speaker, Personal; Chugai, Invited Speaker, Personal; EISAI, Invited Speaker, Personal; Gilead, Invited Speaker, Personal; Seagen, Invited Speaker, Personal; Neopharm Israel, Invited Speaker, Personal; Roche, Other, Personal, Support for attending meetings and/or travel; Pfizer, Other, Personal, Support for attending meetings and/or travel; MSD, Other, Personal, Support for attending meetings and/or travel; Chugai, Other, Personal, Support for attending meetings and/or travel; Novartis, Other, Personal, Support for attending meetings and/or travel; Roche, Advisory Board, Personal; Amgen, Advisory Board, Personal; MSD, Advisory Board, Personal; Chugai, Advisory Board, Personal; EISAI, Advisory Board, Personal; Gilead, Advisory Board, Personal; Seagen, Advisory Board, Personal; Exact Science, Advisory Board, Personal; Roche, Advisory Board, Personal; MSD, Advisory Board, Personal; Gilead, Advisory Board, Personal; Gilead, Other, Personal, Support for attending meetings and/or travel; Daiichi Sankyo, Other, Personal, Support for attending meetings and/or travel; Roche, Steering Committee Member, Financial interest, Personal and Institutional; Novartis, Steering Committee Member, Financial interest, Personal and Institutional; Lilly, Steering Committee Member, Financial interest, Personal and Institutional; AstraZeneca, Steering Committee Member, Financial interest, Personal and Institutional; Gilead, Local PI, Financial interest, Institutional; Pfizer, Local PI, Financial interest, Institutional; Daiichi Sankyo, Local PI, Financial interest, Institutional; Lilly, Local PI, Financial interest, Institutional; MSD, Local PI, Financial interest, Institutional; Novartis, Local PI, Financial interest, Institutional; Non-Financial Interests: Fondazione Michelangelo, Leadership Role, Head of Traslational Research. A.B., B.Ga, H.R.A., M.C., M.B., A.L., L.V., M.D., M.M.N., and B.G. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.