SLM124: A first-in-class anti-CD84 antibody-drug conjugate demonstrates potent anti-tumor activity and favorable tolerability in hematologic malignancy models Free

Background: The Signaling Lymphocytic Activation Molecule Family (SLAMF5), or CD84, is a novel target broadly expressed across a spectrum of hematologic malignancies including Acute Myelogenous Leukemia (AML), Myelodysplastic Syndromes (MDS), Cutaneous T-Cell Lymphoma (CTCL), and Follicular Lymphoma (FL), as well as on immunosuppressive cells within the tumor microenvironment. CD84 is not expressed on normal epithelial, mesenchymal or hematopoietic stem cells. A significant unmet need for effective therapies in these difficult-to-treat cancers remains. SLM124 is a humanized, Fc-engineered IgG1 antibody-drug conjugate (ADC) designed to specifically deliver a potent topoisomerase I inhibitor, exatecan, to CD84-expressing cancer cells.

Methods: We characterized SLM124 through comprehensive preclinical studies and analytics including purity by SEC-HPLC and mass spectrometry. Target binding kinetics, affinity to CD84, and FcγRIIIa binding of Fc-engineered anti-CD84 mAb variants were assessed using Surface Plasmon Resonance (SPR). We assessed CD84 expression on patient tumor samples by immunohistochemistry (IHC). Cell surface CD84 expression and lead mAb binding to various human hematologic cancer cell lines (AML, B-cell and T-cell lymphomas), CHO-K1 cells overexpressing human CD84, as well as normal human B and T cells were evaluated by quantitative flow cytometry (qFACS). In vitro cytotoxicity assays were performed on CD84-expressing cancer cell lines. The in vivo efficacy and tolerability of SLM124 were evaluated in multiple xenograft tumor models.

Results: CD84 target expression is highly overexpressed in tumor cell lines and patient tumor samples. CD84 mRNA is marked increased in tumor cell lines and patient tumor samples in AML, ALL, MDS, MPD, CLL, Hodgkin's Disease, broad spectrum of B and T cell non-Hodgkin's Lymphomas, and CTCL. By IHC, we verified CD84 protein expression is significantly overexpressed in the following blood cancers including AML, CTCL and Follicular Lymphoma patient samples regardless of the molecular phenotype compared to healthy controls. Quantitative FACS analysis demonstrated significant CD84 overexpression across various hematologic cancer cell lines in vitro, including Raji, THP-1, Daudi, SU-DHL-4, Toledo and Ramos, (6 to16-fold higher) compared to the notably low expression on normal human B cells and T cells.

SLM124 monoclonal antibody (mAb) binds to human CD84 with high affinity and specificity. SPR studies confirmed SLM124 mAb exhibits high-affinity binding to human CD84, with KD values in the sub-nanomolar range. No cross-species binding to mouse or cynomolgus monkey CD84 was observed, supporting human specificity. There was no binding of SLM124 mAb to human red blood cells or platelets. The Fc-engineered SLM124 mAb (with LALA mutation), demonstrated significantly reduced binding to FcγRIIIa, indicating substantial Fc silencing to minimize off-target immune effector functions.

SLM124 consistently exhibited potent, dose-dependent cytotoxicity in CD84-expressing cells with IC50s ranging from ~0.61 nM to ~5.8 nM. Dose-dependent cytotoxicity was observed in Raji cells.

In multiple lymphoma xenograft models, single-dose intravenous administration of SLM124 resulted in significant and durable tumor growth inhibition (TGI). Multiple doses given at lower dose levels (fractionated dosing) also demonstrated significant tumor regression. SLM124 was well-tolerated, with no significant body weight loss observed across treatment groups throughout the studies.

Conclusion: SLM124 is a highly potent, first-in-class humanized IgG1 anti-CD84 ADC that precisely targets CD84-expressing hematologic cancer cells. It demonstrates high affinity, specific binding, potency in vitro and is well-tolerated with significant anti-tumor activity in preclinical in vivo lymphoma models. These compelling preclinical data support the continued development of SLM124 as a potentially transformative therapeutic for patients with hematologic malignancies. SLAM Bio anticipates advancing SLM124 therapeutic candidate into the clinic in 2026.