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Targeted Immunotherapeutic Strategies in Breast Cancer
Background: The Ley antigen is expressed in 30-50% of all breast cancers, including a large proportion of breast cancers shown to be negative to Her2-neu. Our group has developed a humanised monoclonal antibody (hu3S193) against the Ley antigen that has exquisite specificity for Ley, internalises into cancer cells, and has potent immune effector function (CDC and ADCC) (ED50 1-3ƒÝg/ml). We have recently completed a Phase I first-in-man trial of hu3S193 in patients with Ley +ve cancers, and shown that hu3S193 specifically localises to metastatic breast cancer, is non-immunogenic, and induces biologic effects in some tumors (including tumor shrinkage). Hu3S193 therefore represents an exciting potential new therapeutic for breast cancer. Objectives: In this project we will investigate the structural and immunological properties of hu3S193, thus leading to optimised therapeutic strategies. Aims: 1) undertake a crystallographic investigation of complement fixation and modulation of pharmacokinetics (pK) of hu3S193; 2) evaluate the effects of upregulating immune function (CDC) of hu3S193 through inhibiting the complement regulatory protein CD59; 3) investigate the therapeutic efficacy of alpha-labelled (213Bi)-hu3S193. Study Design: Aim 1). To evaluate the pK and potent CDC of the hu3S193 IgG1, we will perform a structure-based investigation of the interactions of hu3S193 with FcRn and C1q. We will determine the crystal structure of intact hu3S193 IgG1 with bound Ley ligand to elucidate the spatial relationships between Fab and Fc in an immune complex, design a series of mutations for modifying the pK of hu3S193 IgG1, and crystallize the complex of C1q globular head regions bound to the hu3S193:Ley immune complex. Aim 2). Our research has shown that an anti-CD59 Fab we have developed significantly increases the cytotoxicity of hu3S193, and this novel concept will be explored through the characterisation of the anti-CD59 Fab, and the effects of combining anti-CD59 Fab with hu3S193 in-vitro and in in-vivo models. Aim 3). The therapeutic efficacy of 213Bi-labelled hu3S193 will be evaluated by radiolabelling of hu3S193 with 213Bi, and assessment of biodistribution and in-vivo efficacy of 213Bi-hu3S193 in both established and micrometastatic breast cancer xenograft models. Potential Outcomes and Benefits of the Research: This project will establish the rationale for optimal therapy of breast cancer with hu3S193 through enhancement of immune effector function and selective delivery of radioisotopes to tumors, which will be subsequently evaluated in clinical trials.
The development of recombinant antibodies for cancer therapy has emerged as one of the most promising areas in oncology therapeutics. Our program has developed a recombinant humanised monoclonal antibody against the Ley antigen (hu3S193) which is expressed in 30-50% of breast cancers, including a large proportion of breast cancers shown to be negative to Her2-neu. Hu3S193 has exquisite specificity for Ley, and importantly has been shown to have potent immune effector function causing breast cancer cell killing in laboratory assays. We have recently completed a Phase I first-in-man trial of hu3S193 in patients with advanced cancers, and demonstrated that hu3S193 maintains potent immune effector function, localises to sites of breast cancer throughout the body, and is non-immunogenic. Importantly, hu3S193 also induced some biologic effects in tumors in patients entered into this trial. Hu3S193 therefore represents an exciting potential new therapeutic for breast cancer. The optimal tumor cell killing mechanisms of recombinant antibodies are highly dependent on the structure of the antibody and its binding to target antigen/receptor. The specificity of hu3S193 for tumour sites allows a number of therapeutic approaches to be explored, including delivery of high energy-low path length alpha-emitters (eg 213Bi) for treatment of small volume disease. The physical structure of the hu3S193 antibody also has direct implications on immune effector function, and the clearance of the antibody from the blood. This information is crucial to understanding and improving the targeting and cell killing ability of hu3S193. The ability of hu3S193 to induce potent immune effector function at breast cancer sites could be further improved by inhibiting factors which reduce the efficacy of complement (eg CD59). To this end have developed an antibody fragment that is a potent inhibitor of CD59 and therefore has the potential to upregulate hu3S193 complement dependent cytotoxicity, leading to a substantial improvement in the efficacy of hu3S193 therapy. In this project we will identify the mechanisms important for the immunological activity of hu3S193, and clearance of hu3S193 from blood. With this information we will determine the rationale for optimal therapy of breast cancer with hu3S193 through enhancement of immune effector function and selective delivery of radioisotopes to tumors. This will lead to the conduct of clinical trials that will hopefully result in new and improved therapeutic options for patients with breast cancer.