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Immunotherapy


studies showed activity against several tumours, including lenalidomide-resistant multiple myeloma, triple negative breast cancer and AML. An ongoing study is testing monotherapy and will expand to treat CD20-positive NHL patients in combination with rituximab (NCT02367196)10-11. The main challenge with IgG4 CD47 antibody


therapies include its effect on red blood cells, some- times causing transient anaemia. Some pro- grammes have managed this anaemia using a prim- ing dose strategy that culls older red blood cells and stimulates production of additional red blood cells before initiating full-strength therapy12. One advantage to these therapies is the limited side- effect profile at high doses because they generally do not attack healthy host cells.


SIRP-Fc fusion proteins Currently there are three SIRP-Fc fusion proteins in clinical trials: The first, TTI-621, combines a wild-type human


SIRP that binds to CD47 with an active IgG1 Fc domain, which presents a potent phagocytotic sig- nal to effector cells. Preclinical trials demonstrated how TTI-621 stimulated macrophages to attack tumour cells preferentially to normal cells and slowed growth of AML and lymphoma xenografts. TTI-621 does not bind to red blood cells, though it does attach to leukocytes and platelets13. In Phase I trials that began in 2016, TTI-621 has been proven effective as a monotherapy and when com-


Drug Discovery World Spring 2019


bined with rituximab in treating diffuse large B-cell lymphoma14. However, toxicity limited escalation of the dose in humans above 0.3mg/kg. Further investigation of TTI-621 is now focused on local delivery by direct intra-tumoral injection15. The second, TTI-622, combines a wild-type


human SIRP to a IgG4 Fc domain, avoiding nor- mal tissue toxicities associated with IgG1. A Phase I dose escalation trial of TTI-622 is under way in patients with advanced relapsed or refractory lym- phoma or myeloma with plans to expand into com- bination treatments with rituximab, anti-PD-1 anti- bodies and proteasome inhibitors (NCT03530683). The final one, ALX148, is a fusion protein made


up of 1) an engineered SIRP domain with more than a 7,000-fold greater affinity for human CD47 than wild-type SIRP and 2) an inactive IgG1 Fc domain. In preclinical trials, given the inactive Fc domain, it did not cause anaemia and displayed modest activity as monotherapy. But it was broad- ly active in xenograft models in combination with tumour-targeting antibodies, such as obinutuzum- ab, trastuzumab, cetuximab and anti-PD-L1 anti- bodies that provide an additional ‘eat me’ signal16. Clinical trials, in combination with pembrolizum- ab, trastuzumab and rituximab, are ongoing in advanced solid tumour and lymphoma patients17.


Down for the count: a preliminary proforma analysis The therapeutic and market potential for combining


19


Figure 2


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