IKS03, a Next Generation CD19-Targeted Antibody Drug Conjugate, Shows Potent Activity in Preclinical Models of Aggressive B-Cell Lymphomas (2022)

Diffuse large B-cell lymphoma (DLBCL) is a common subtype of non-Hodgkin lymphoma (NHL). Although many patients respond to frontline chemoimmunotherapy, and treatment options for patients with relapsed or refractory DLBCL have improved with the success of CAR T cell therapies, clinical outcome for many patients is still suboptimal. CD19 is widely expressed in DLBCL tumor cells, with normal tissue expression limited to B-cells, making it an attractive target for targeted therapies including antibody drug conjugates (ADC). IKS03 is a CD19-targeting ADC with a PBD dimer pro-drug payload that induces DNA crosslinking and blocks DNA replication ultimately leading to cell death. Following tumor selective binding and uptake, IKS03 requires intracellular lysosomal processing of beta-glucuronidase protecting groups to fully activate the payload which minimizes systemic release of the PBD dimer in human plasma. IKS03 is derived from a human antibody that binds with nanomolar affinity to human and cynomolgus monkey CD19. It is generated by site-specific bioconjugation yielding a homogeneous conjugate with a drug to antibody ratio of 2. In vitro, IKS03 induces specific and dose dependent cell killing of diverse CD19+ lymphoma cell lines with sub-nanomolar EC50 values. Conversely, in vitro cytotoxicity of the conjugate against normal human primary peripheral blood mononuclear cells was attenuated with an EC50 of approximately 1 μM, similar to a non-PBMC binding ADC bearing the same PBD pro-drug. The unconjugated payload more potently reduced PBMC viability with a sub-nanomolar EC50. This is consistent with low non-specific payload release from the conjugate underscoring the improved properties of the PBD pro-drug design. Pharmacokinetics of IKS03 was assessed in a repeat dose toxicity study in monkeys and the plasma concentrations of total ADC and total antibody were determined by LC-MS/MS across the 3-week dosing interval. Overall mean half-life for total ADC was approximately 8 days and clearance rate was slow (mean 0.2 mL/h/kg). Total ADC peak concentration, total plasma exposure and half-life were comparable to that of total antibody demonstrating favorable ADC stability in plasma with limited systemic payload release. In vivo efficacy was evaluated in CD19-expressing preclinical human xenograft models representing different subtypes of B-NHL. Granta-519 cells contain the CCND1 t(11;14) translocation often present in mantle cell lymphoma (MCL). IKS03 was highly active against Granta-519 xenografts in SCID mice with complete tumor regressions observed with a single dose of 0.1 mg/kg. Efficacy was further evaluated in CD19-positive, low passage DLBCL patient-derived xenograft (PDX) models of known genomic profiles. IKS03 was highly active yielding complete tumor regressions following a single dose of 0.3 mg/kg in a refractory lymphoma Bcl2+ PDX model derived from a patient with no response to prior CHOP treatment. Post tumor collection, this patient was also refractory to EPOCH chemotherapy. A second xenograft model was derived from a treatment naïve high-grade 'triple hit' lymphoma patient (BCL2+; BCL6+; MYC+; XP01 amplified). Post tumor collection, this patient was refractory to R-CHOP therapy with disease progression within 2 months. Tumors rapidly progressed in this model, yet single dose treatment with IKS03 resulted in significant tumor growth inhibition at 0.3 mg/kg and complete tumor regressions at 1 mg/kg. Likewise, in a pre-treated MYC-amplified GCB lymphoma model, a single IKS03 dose of 0.3 mg/kg inhibited tumor growth and 1 mg/kg yielded complete inhibition of tumor growth. In conclusion, IKS03 is highly effective in preclinical MCL and DLBCL xenograft models that contain some of the genetic alterations commonly found in relapsed/refractory NHL patients in need of treatment. Preclinical data further demonstrates that IKS03's advanced ADC design results in specific target-dependent in vitro activity, excellent plasma stability and allows for effective targeting of B-cell tumors while sparing normal CD19-negative cells.