3P - Correlation between antibody-drug conjugate (ADC) targetable antigen expression and occurrence of interstitial lung disease (ILD)

Background

Although approved for multiple tumor types, one of the most limiting toxicities of antibody-drug conjugates (ADC) is development of interstitial lung disease (ILD). With several ADCs currently under development, it is important to identify mechanism of ILD to optimize drug development. We examined the correlation between target antigen expression level in normal lung tissue and the occurrence of ILD for ADCs studied in lung cancer.

Methods

We performed a literature search of ADCs in lung cancer to identify different antigen targets currently under investigation. Data was abstracted for incidence of ILD from publically available trial results of phase I-II clinical trials of ADCs in non-small cell lung cancer (NSCLC) targeting antigens: ERBB2 (trastuzumab deruxetecan), ERBB3 (patritumab deruxetecan), TROP2 (datopotamab deruxetecan), CEACAM5 (tusamitamab ravtansine), and MET (Telisotuzumab Vedotin). We used the highest value of all grade ILD reported at any dose to maximize identification of any correlation with antigen expression. We obtained scRNA-seq expression [(normalized mean transcript protein expression (nMTP)] values in predominant lung cell type from the Human Protein Atlas version 22.0 using enrichment prediction score for each cell type profiled in the lung tissue.

Results

Across different ADCs, the incidence of all grade ILD ranged from 0-26.4%. All ADC target antigens were expressed in lung tissues with highest normalized transcript expression level within lung tissue found in alveolar cells (type 1 or type 2). Across various targets, nMTP expression ranged from 73.7-1549.8. In terms of correlation between target expression and incidence of ILD, no correlation was found between these 2 variables (Pearson correlation coefficient = -0.007).

Conclusions

No correlation was identified between scRNA-seq expression of ADC-targetable antigens on alveolar cells and incidence of ILD. This may imply and further provide support to ILD being a bystander effect rather than true on-target toxicity with ADCs. Further ADC development should focus on reducing bystander effects via selection of linker and payload classes least likely to cause ILD while optimizing dose and drug-to-antibody ratio.

Clinical trial identification

Editorial acknowledgement

N/A

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Peters: Financial Interests, Institutional, Advisory Board: Vaccibody, Takeda, Seattle Genetics, Sanofi, Roche/Genentech, Regeneron, Phosplatin Therapeutics, PharmaMar, Pfizer, Novartis, Mirati, Merck Serono, MSD, Janssen, Incyte, Illumina, IQVIA, GlaxoSmithKline, Gilhead, Genzyme, Foundation Medicine, F-Star, Eli Lilly, Debiopharm, Daiichi Sankyo, Boehringer Ingelheim, Blueprint Medicines, Biocartis, Bio Invent, BeiGene, Bayer, BMS, AstraZeneca, Arcus, Amgen, AbbVie, iTheos, Novocure; Financial Interests, Institutional, Invited Speaker: Takeda, Sanofi, Roche/Genentech, RTP, Pfizer, PRIME, PER, Novartis, Medscape, MSD, Imedex, Illumina, Fishawack, Eli Lilly, Ecancer, Boehringer Ingelheim, BMS, AstraZeneca, OncologyEducation, RMEI, Mirati; Financial Interests, Personal, Other, Associate Editor Annals of Oncology: Elsevier; Financial Interests, Institutional, Invited Speaker, MERMAID-1: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MERMAID-2, POSEIDON, MYSTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451: BMS; Financial Interests, Institutional, Invited Speaker, RELATIVITY 095: BMS; Financial Interests, Institutional, Invited Speaker, BGB-A317-A1217-301/AdvanTIG-301: BeiGene; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair ZEAL-1: GSK; Financial Interests, Institutional, Invited Speaker, Clinical Trial steering Committee PEARLS, MK-7684A: MSD; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering Committee SAPPHIRE: Mirati; Financial Interests, Institutional, Invited Speaker, LAGOON: Pharma Mar; Financial Interests, Institutional, Invited Speaker, phase 1/2 trials: Phosplatin Therapeutics; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair Skyscraper-01; chair ALEX; steering committee BFAST; Steering Committee BEAT-Meso; steering committee ImPower-030, IMforte: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Phase 2 Inupadenant with chemo: iTeos; Non-Financial Interests, Personal, Officer, ESMO President 2020-2022; Non-Financial Interests, Personal, Officer, Council Member & Scientific Committee Chair: ETOP/IBCSG Partners; Non-Financial Interests, Personal, Officer, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Other, Involved in Swiss politics: Swiss Political Activities; Non-Financial Interests, Personal, Officer, President and Council Member: Ballet Béjart Lausanne Foundation; Non-Financial Interests, Personal, Principal Investigator, Involved in academic trials: ETOP / EORTC / SAKK; Non-Financial Interests, Personal, Member: Association of Swiss Physicians FMH (CH), ASCO, AACR, IASLC; Non-Financial Interests, Personal, Leadership Role, ESMO President: ESMO; Non-Financial Interests, Personal, Member, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Leadership Role, Vice-President: SAMO; Non-Financial Interests, Personal, Member, Association of Swiss interns and residents: ASMAC/VSAO. A. Dimou: Financial Interests, Personal, Advisory Board: TP Therapeutics, Guardant; Financial Interests, Personal, Advisory Role: Intellisphere Llc. A. Desai: Financial Interests, Personal, Advisory Board: Amgen, Sanofi. All other authors have declared no conflicts of interest.