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Immune modulatory Anti-CCR4 antagonistic Antibodies
- Fully human IgG1 antagonistic antibodies with sub nM affinity for CCR4
- Dual function-blocking and ADCC MoA advantageous in highly immunosuppressive microenvironments
- Broad clinical utility and strong rationale for combination with immune checkpoint modulators
- Extensive patent portfolio providing target, composition of matter, therapeutic and diagnostic claims
We are seeking a commercial partner for licensing and/or collaborative development of potential best-in-class therapeutic anti-CCR4 antibodies. The opportunity comes with an extensive data package, demonstrating in vivo efficacy in both haematological and solid tumour models, offering a rapid route to the clinic for a commercial partner, either as a monotherapy or in combination with other immune-stimulatory agents.
Antibody variants against human CCR4 were generated using phage display . The CCR4 specific antibodies bind both non-human primates and mouse CCR4, compete with CCL17 and CCL22 ligand binding, block ligand-induced signalling and cell migration, and demonstrate efficient killing of CCR4-positive tumour cells via ADCC and phagocytosis.
In an orthotopic syngeneic model of renal cell carcinoma (RCC), where CCR4 and its ligand CCL17 are highly expressed, treatment with the lead antibody significantly reduced tumour burden, indicating single agent activity, and caused a significant reduction in the plasma concentration of CCL17, suggesting its utility as a PD marker (Figure 1). The inventors have also demonstrated that a high CCL17:CCL22 ratio correlates with poorer survival outcomes in RCC patients.
Significant reduction in tumour burden has also been demonstrated for the lead antibody in an adult T cell lymphoma xenograft model.
Data are available from in vivo PK and PD mouse studies, and pre-clinical dose range finding studies in cynomolgus monkey.
Mechanism of action studies have demonstrated that treatment with these anti-CCR4 antibodies may promote an anti-tumour immune switch via multiple mechanisms:
- increase in Th1 type cytokines versus Th2 type cytokines and an increase in IFNγ+ CD4+ T cells, which drive anti-tumour immunity;
- an increase in NK cells and a reduction in MDSCs, which are instrumental in protecting the tumour from the immune system;
- modulation of tumour-associated macrophage phenotype including an increase in MHC Class II and iNOS expression, and a decrease in mannose receptor and arginase expression (Figure 2)
Combination with a neutralising antibody to mouse MHC Class II, or use of anti-CCR4 in T-cell deficient nude mice, completely abrogated the effects of the anti-CCR4 antibody, suggesting that CD4+ T cells are critical in mediating the described immunological effects.
Both defucosylated and fucosylated versions of the antibody demonstrated therapeutic efficacy showing that the effects are, at least in part, independent of the antibody’s ability to induce ADCC, and that ligand blocking is an important aspect of this antibody’s profile. This suggests an advantage over KW-0761, a fucosylated humanised anti-CCR4 antibody approved in Japan for the treatment of relapsed or refractory CCR4-positive lymphomas. KW-0761 demonstrates enhanced ADCC activity but lacks the function blocking properties of the antibody described here.
Chemokine receptors are involved in a wide variety of inflammatory and immune responses through chemo-attraction of innate and adaptive immune cells. In cancer, chemokines and their receptors are responsible for trafficking immune and tumour cells into and out of the tumour microenvironment (TME) . While current immune checkpoint inhibitor strategies drive the immune system, inhibitors of chemokine receptors have the ability to direct the immune response to the tumour.
The chemokine receptor CCR4 represents a potentially important target for cancer immunotherapy due to its expression on both tumour infiltrating immune cells, including regulatory T cells (Tregs) and pro-tumour M2 macrophages [3, 4], and tumour cells. CCR4 and its ligands, CCL17 and CCL22, play a key role in development and progression of solid tumours by recruiting and trafficking immune cells into the lymphoid infiltrates surrounding the tumour. It has been proposed that the tumour cells and tumour infiltrating macrophages produce the chemokine CCL22, which attracts and recruits Tregs expressing CCR4, thereby facilitating immune evasion [5, 6]. As antibodies targeting CCR4 may possess dual or multiple modes of action in some cancer indications, such as targeting CCR4 expressing tumour cells and modulation of the immunosuppressive TME, CCR4 represents an attractive immunotherapy target.
CCR4 is highly expressed in haematological cancers of T cell origin, and solid tumour indications including renal, gastric, cervical, oesophageal, breast and colorectal and has been associated with poor prognosis [7, 8]. CCR4 therefore represents an ideal target for antibody-based immunotherapy for both haematological and solid tumours.
The work on CCR4 is underpinned by discoveries from the lab of Prof. Fran Balkwill, Queen Mary University of London.
1. PMID: 25080123
2. PMID: 21989643
3. PMID: 11786428
4. PMID: 9419219
5. PMID: 15322536
6. PMID: 16740709
7. PMID: 21479551
8. PMID: 19474687