Abstract 841P
Background
Bispecific CD20xCD3 IgG antibodies are clinically efficacious but are associated with significant toxicity, especially cytokine release syndrome. IGM-2323 is a novel engineered high-affinity, high-avidity anti-CD20 pentameric IgM antibody, with an anti-CD3 scFv fused to the joining (J) chain. IGM-2323 kills CD20 expressing target cells through T-cell dependent cellular cytotoxicity (TDCC) and complement-dependent cytotoxicity (CDC), with minimal cytokine release. We present preclinical data demonstrating potent B-cell killing by IGM-2323, including normal and malignant B-cells with very low CD20 expression and that are resistant to other CD20-directed antibodies.
Methods
Human B-cell lines with a broad range of CD20 expression levels, including a CD20-low and rituximab-resistant Ramos cell variant, were evaluated in vitro for TDCC or CDC induced by IGM-2323. The ability of IGM-2323 to eliminate normal B-cells in cynomolgus monkeys was also assessed.
Results
IGM-2323 induced highly potent killing of a panel of human B-cell tumor lines with varying CD20 expression levels. Even B-cell lines with low CD20 densities were effectively eliminated by IGM-2323. Furthermore, a rituximab-resistant cell line, with significantly reduced CD20 expression levels, was killed more potently by IGM-2323 compared to a bispecific IgG and at lower effector-to-target ratios. IGM-2323 cytotoxicity was associated with low levels of cytokines, in contrast with significant cytokine release observed with a bispecific IgG. IGM-2323 also had the ability to induce durable B-cell depletion in cynomolgus monkeys, with minimal elevation of cytokines.
Conclusions
We demonstrate that IGM-2323 has highly potent in vitro and in vivo TDCC and CDC activities against CD20 expressing B-cells, resulting in elimination of CD20-low and rituximab-resistant B cell lines. IGM-2323 is currently being studied in a phase 1 clinical trial in relapsed/refractory non-Hodgkin’s lymphoma, where it has been generally well tolerated with both complete and partial responses observed (NCT04082936). Clinical studies will continue to evaluate these findings, including indications with low CD20 expression.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
IGM Biosciences.
Funding
IGM Biosciences.
Disclosure
K. Li: Financial Interests, Personal, Full or part-time Employment: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: IGM Biosciences; Financial Interests, Personal, Royalties, Received Royalty payment from UCLA on my patent: University of California, Los Angeles. M.F. Kotturi, M. Manlusoc, R. Yun, P.R. Hinton: Financial Interests, Personal, Full or part-time Employment: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: IGM Biosciences. K. Logronio: Financial Interests, Personal, Full or part-time Employment: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: Spotlight Therapeutics. R. Baliga: Financial Interests, Personal, Advisory Role, Consulting services: IGM Biosciences; Financial Interests, Personal, Leadership Role: Rubryc Therapeutics; Financial Interests, Personal, Stocks/Shares: Cytokinetics; Financial Interests, Personal, Stocks/Shares: Catalyst Biosciences; Financial Interests, Personal, Stocks/Shares: Sutro Biopharma; Financial Interests, Personal, Stocks/Shares: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: Rubryc Therapeutics; Financial Interests, Institutional, Other, Collaboration: Zai Lab; Non-Financial Interests, Personal, Member: AACR; Financial Interests, Personal, Member: SITC. G. Hernandez: Financial Interests, Personal, Full or part-time Employment: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: Genentech; Financial Interests, Personal, Stocks/Shares: IGM Biosciences; Non-Financial Interests, Proprietary Information: IGM Biosciences; Non-Financial Interests, Member: AACR; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: SITC. A.M. Sinclair: Financial Interests, Personal, Full or part-time Employment: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: IGM Biosciences; Other, Personal, Other, am employed by IGM Biosciences and hold stock and speak on it's behalf at meetings: IGM Biosciences. S.F. Carroll: Financial Interests, Personal, Advisory Role, Consulting: Synergys Biotherapetucs; Financial Interests, Personal, Full or part-time Employment: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: IGM Biosciences. W.R. Godfrey: Financial Interests, Personal, Full or part-time Employment: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: Gilead Sciences. B.A. Keyt: Financial Interests, Personal, Invited Speaker, Honoraria for speaking at the LakePharma conference: Lake Pharma; Financial Interests, Personal, Full or part-time Employment, full time employee as Chief Science Officer: IGM Biosciences; Financial Interests, Personal, Stocks/Shares: IGM Biosciences.