200P - Precise tumor & patient selection for CDR404: A bispecific & bivalent MAGE-A4 T cell engager

Background

A phase 1 trial of CDR404, an antibody-based T-cell engager (TCE) targeting MAGE-A4, is planned for 2024. CDR404 binds to a MAGE-A4 peptide presented on cancer cell surface HLA-A2. There are no validated assays to measure HLA peptide presentation. RNA sequencing or immunohistochemistry (IHC) for total MAGE-A4 can be used as surrogates. To identify tumors for trial inclusion and enable precise patient selection, we performed bioinformatic analyses and compared two IHC antibodies.

Methods

32 solid tumors were selected from the TCGA dataset and ranked based on MAGE-A4 mRNA prevalence and expression (high to low). To assess protein expression, we compared specificity of two commercial MAGE-A4 antibodies for patient selection: an anti-rabbit E7O1U clone and an anti-mouse OTI1F9 clone. Cross reactivity to MAGE-A family members was confirmed using IHC of individually transfected HEK293 cells.

Results

In ranking order, we identified 6 (RNA^HIGH) tumors: squamous lung (LUSC), squamous head & neck (HNSC), bladder (BLCA), uterine carcinosarcoma (UCS), testicular germ cell (TGCT) and squamous cervical (CESC), which had both MAGE-A4 mRNA highest prevalence and median expression. Both parameters were positively correlated (R²=0.64, p=0.00012). Mean RNA levels were different for the RNA^HIGH group compared to the remaining 26 tumors (RNA_LOW group), which consisted mainly of adenocarcinomas (p=9.1e^-120). Of interest, human papillomavirus (HPV) negative (-VE) HNSC had higher RNA levels vs. HPV-positive (+VE) tumors (p=0.0046). In vitro over-expression experiments demonstrated that E7O1U only bound to MAGE-A4 whereas OTI1F9 cross-reacted widely with MAGE-A3, -A6, -A8, -A10, -A11 and -A12.

Conclusions

Squamous cell carcinomas were enriched in the MAGE-A4 RNA^HIGH group. Trial screening efficiency can be optimized by enrolling RNA^HIGH tumors especially LUSC and HPV -VE HNSC, two cancers with high unmet medical need. Lack of response reported in another MAGE-A4 TCE trial (NCT03973333) where tumor screening in ovarian cancer was absent confirms that IHC selection will be essential for RNA_LOW tumors. In this regard, we have identified E7O1U as a highly specific MAGE-A4 antibody for precise IHC patient selection in the CDR404 trial.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

CDR-Life.

Funding

CDR-Life.

Disclosure

G. Giacomazzi, N. Dupuis, D. Rondas, P. Swatkowski: Financial Interests, Personal, Full or part-time Employment: CellCarta. M. Liivrand, R. Hieta: Financial Interests, Personal, Full or part-time Employment: Genevia Technologies. M. Vrohlings: Financial Interests, Personal, Full or part-time Employment: CDR-Life; Non-Financial Interests, Member: ESMO. D. Lenherr-Frey: Financial Interests, Personal, Full or part-time Employment: CDR-Life; Other, Personal, Project Lead: CDR-Life. L. Borras: Financial Interests, Personal, Full or part-time Employment: CDR-Life; Financial Interests, Personal, Leadership Role: CDR-Life; Financial Interests, Personal, Stocks/Shares: CDR-Life. S. Biswas: Financial Interests, Personal, Full or part-time Employment: CDR-Life. R. Leidner: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Project Lead: Bristol Myers Squibb, Incycte. E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, Servier, TargImmune, T-knife, Chugai, Elevation Oncology, Ellipses Pharmacy, SyneosHealth, Genmab, Diaccurate; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanofi, Merus; Financial Interests, Personal, Steering Committee Member: Novartis; Non-Financial Interests, Other, Non-for-profit Foundation. President and co-founder: INTHEOS (Investigational Therapeutics in Oncological Sciences) non-for-profit Foundation; Non-Financial Interests, Advisory Role: PsiOxus; Non-Financial Interests, Other, Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests, Member of Board of Directors, Non-for-profit Foundation, trustee member: Non-for-profit Foundation PharmaMar; Non-Financial Interests, Advisory Role, Non-for-profit foundation: CRIS Cancer Foundation, non-for-profit ; Non-Financial Interests, Member: ASCO, ESMO, SEOM, EORTC.