Abstract
Although blinatumomab is an approved treatment for Philadelphia chromosome negative relapsed or refractory (r/r) precursor-B cell ALL and is under development for r/r B cell NHL, blinatumomab has several limitations impacting fuller therapeutic utility. For instance, blinatumomab therapy requires continuous infusion due to its rapid clearance owing to its size and lack of an antibody Fc and has been associated with potentially life-threatening CNS toxicities and cytokine release syndrome (Viardot A et al, Blood 2016; Goebeler ME et al, J Clin Oncol 2016; Topp et al, Lancet Oncol 2015). In addition, blinatumomab treatment is associated with higher incidence of relapse in patients with high disease burden, and its T cell redirected killing is limited by T cell immunosuppression (e.g. PD-1/PD-L1 up-regulation [Köhnke et al, J Hematol & Oncol 2015]; Treg suppression [Duell et al, ASH abstract 2014]). ZW38 is designed to address each of these limitations and represents a best in class CD19-directed CD3 T cell engager and a novel class of bispecific antibody drug conjugate (ADC).
ZW38 contains an Azymetric IgG1-like Fc that carries mutations in the CH2 domain preventing FcgR dependent ADCC and ADCP and exhibits typical IgG1-like PK in rodent studies. Transient expression in mammalian CHO cells demonstrate ZW38 can be expressed at a titre of hundreds mg/L and can be purified using conventional IgG antibody methods and resins with typical IgG step purification yields and high heterodimer purity. Additionally, ZW38 has been conjugated to a microtubule inhibitor that lacks bystander killing.
ZW38 antibody paratopes have been engineered to favor T cell-B cell functional engagement and selective target B cell cytotoxicity. In vitro studies demonstrated that ZW38 binds to human CD19+ B cells with >30-fold higher affinity than to human CD3+ T cells. Similar to blinatumomab, ZW38 can redirect the killing of target cancer B cells via T cell subtypes from human PBMC and its cytotoxicity is target B cell dependent. At concentrations that result in efficacious B cell depletion, ZW38 does not overly activate T cells. ZW38 is specifically engineered to induce more 'controlled' T cell activation than blinatumomab while still mediating sufficient T cell redirected target B cell depletion. ZW38 mediates T cell activation, cytokine release, and proliferation at nanomolar potency. By design, the sufficient, lower cytokine levels necessary for B cell killing may reduce the risk of cytokine release syndrome and T cell anergy. ZW38 exhibited potent growth inhibition in a panel of different B cell ALL and NHL cancer lines including but not limited to: G2, Nalm-6, RS4-11, Daudi, SUDHL-4 and SUDHL-6. In comparison to blinatumomab, ZW38 exhibits superior target B cell depletion in in vitro co-cultures of Raji lymphoma cells and human PBMC (ZW38 depletes > 90% B cells; blinatumomab depletes 20-90% B cells depending on the PBMC donor). In addition, ZW38 was effective in killing target B cells in PBMC cultures in which PD-1 has been up-regulated, which were resistant to blinatumomab killing in this assay. The dual mechanisms of action of ZW38, redirected T cell cytotoxicity and ADC cytotoxicity, may prolong and/or boost response rates, lower the incidence of relapse, and reduce the likelihood of acquired resistance while its 'controlled' T cell activation profile may reduce the risk of life-threatening and potentially fatal neurotoxicity and CRS.
Disclosures
Ng: Zymeworks: Employment, Patents & Royalties. Spreter:Zymeworks: Employment, Patents & Royalties. Davies:Zymeworks Biopharmaceuticals: Employment. Wickman:Zymeworks: Employment.
Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice