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(12) Patent Application Publication (10) Pub. No.: US 2015/0183875 A1 Cobbold Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0183875 A1 Cobbold Et Al US 2015 0183875A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0183875 A1 Cobbold et al. (43) Pub. Date: Jul. 2, 2015 (54) IMMUNOTHERAPEUTIC MOLECULES AND Publication Classification USES (51) Int. Cl. (71) Applicant: THE UNIVERSITY OF C07K 6/28 (2006.01) BIRMINGHAM, Birmingham (GB) A6II 45/06 (2006.01) A 6LX39/395 (2006.01) (72) Inventors: Mark Cobbold, Birmingham (GB); (52) U.S. Cl. David Millar, Birmingham (GB) CPC ......... C07K 16/2809 (2013.01); A61 K39/3955 (2013.01); A61K 45/06 (2013.01); C07K 16/2896 (2013.01); C07K 23.17/30 (2013.01); (21)21) Appl. NoNo.: 14/3814059 s C07K 2317/622 (2013.01)s (22) PCT Fled: Feb. 28, 2013 (57) ABSTRACT (86). PCT No.: PCT/GB2O13/OSO499 The invention provides molecule comprising: (i) a targeting moiety capable of directly or indirectly targeting to unwanted S371 (c)(1), cells, and (ii) a further moiety that has a masked immune cell (2) Date: Aug. 27, 2014 binding region so as to prevent binding of the further moiety to an immune cell, wherein the masked immune cell binding (30) Foreign Application Priority Data region is capable of being selectively unmasked when the molecule is in the vicinity of the unwanted cells so as to allow Feb. 28, 2012 (GB) ................................... 12O3442.7 binding of the further moiety to an immune cell. FURTHERMOIETY (3) T CELL BINDING REGION (4) Protease td) TARGETING MOIETY (1) UNWANTED CELL (2) Patent Application Publication Jul. 2, 2015 Sheet 2 of 14 US 2015/O183875 A1 3. :O N CD - O 5. 9) so ll 5 O U?) Patent Application Publication Jul. 2, 2015 Sheet 3 of 14 US 2015/O183875 A1 CP H s g r O) a 23 S. Ne O) CC - 9 l CD S Z 5Y O CC > Na > . CC D Patent Application Publication Jul. 2, 2015 Sheet 4 of 14 US 2015/O183875 A1 i Patent Application Publication Jul. 2, 2015 Sheet 5 of 14 US 2015/O183875 A1 Patent Application Publication Jul. 2, 2015 Sheet 6 of 14 US 2015/O183875 A1 G3Infi? (ZJOZQued) Patent Application Publication Jul. 2, 2015 Sheet 7 of 14 US 2015/O183875 A1 |||1 | WdWNWdWINdW R^5?GOTTINGG?ITA6Iolo|IHN2001||HALOTWILLITATOnwil 9 Patent Application Publication Jul. 2, 2015 Sheet 8 of 14 US 2015/0183875 A1 O O y H H W -G-GAO-do Jed duOO XeWO 9/o Patent Application Publication Jul. 2, 2015 Sheet 9 of 14 US 2015/0183875 A1 0 Z?un61-3 (ZJOZQued) .\7-OLIH-duuOO\7–0LIH-duuOO 6?IOJO £CIO Patent Application Publication Jul. 2, 2015 Sheet 10 of 14 US 2015/O183875 A1 Capped Bispecific Antibody (CD19-CD3) T Cells -- B.mab Targets + B. mab + T Cells Target + B. mab O 500 OOO 1500 IFN-y (pg/ml) Figure 8 Patent Application Publication Jul. 2, 2015 Sheet 11 of 14 US 2015/0183875 A1 6?un6||-|| (ZgoIqued) 6IOJO Patent Application Publication Jul. 2, 2015 Sheet 12 of 14 US 2015/0183875 A1 6?un61-I (zgozQued) 6ICIO Jul. 2, 2015 Sheet 13 of 14 US 2015/O183875 A1 F5FED???L?S Patent Application Publication Jul. 2, 2015 Sheet 14 of 14 US 2015/O183875 A1 OIaun61 (ZJOZQued) US 2015/O 183875 A1 Jul. 2, 2015 IMMUNOTHERAPEUTIC MOLECULES AND Blood (2000),95: 2098-103) and also in treating non-tumour USES diseases (Bruhl, J Immunol (2001), 166:2420-6). The anti 0001. The present invention relates to immunotherapeutic bodies rely on one scFv unit being capable of activating T molecules. In particular, it relates to immunotherapeutic mol cells, by specifically binding to an antigen on the T cells, and ecules that can be used to prevent or treat a condition charac the other scFv unit specifically binding to an antigen on a terised by the presence of unwanted cells. Such as tumours or target cell intended for destruction. In this way, the antibodies other disease causing cells. are able to activate and redirect the immune system's cyto 0002 Immunotherapeutic strategies for targeting malig toxic potential for the destruction of pathological cells. nant disease are an active area of translational clinical 0005. Two BITE antibodies are currently being tested in research, and have been for several decades. The current clinical trials. Blinatumomab (also known as MT103) is models dictate that cancer represents either a functional or bispecific for CD3 on T cells and CD19 on B cells, and is constitutional immunodeficiency which can be treated with being tested for the treatment of non-Hodgkin’s lymphoma immunotherapeutic manipulation of the host. These efforts and acute lymphoblastic leukaemia. MT110 is bispecific for can be broadly classified into two groups. The first serves to CD3 and epithelial cell adhesion molecule (EpCAM), and is augment or Support endogenous anti-tumour immunity being tested for the treatment of lung and gastrointestinal through measures such as vaccination, cytokine Support (IL cancer patients. 2, IFNY) or reducing immunosuppressant environment (ipili 0006. However, a limitation of BITE antibodies and simi mumab) whilst the second seeks to restore an absolute defi lar bispecific therapeutic antibodies is that they can activate T ciency with components of a functional immune response cells when binding to any target that expresses the targeting (passive immunotherapy with antibodies, TCR transfer, Stem antigen. For instance, if the BITE or bispecific antibody was Cell Transplantation and adoptive immunotherapy). These designed to target the EGF receptor, which is expressed at approaches are unified by the argument that a highly effective high levels in many epithelial cancers but also expressed at functional anti-tumour immune response is indeed possible. moderate levels in healthy tissues, both healthy and cancers Although irrefutable evidence exists for an effective anti tissue are targeted. Moreover, the agent becomes active when tumour immune response in Some cases, this central pillar of bound to any surface and thus non-specific binding to Sur tumour immunology is overwhelmingly countered by the faces in a non-antigen binding manner can lead to T-cell current clinical reality that despite great efforts, no effective activation and off-target effects. For these reasons, all BITE immunotherapeutics are available for the majority of patients antibodies in development are given at very low concentra with cancer. Almost all cancer vaccination trials have pro tions. vided negative results, with those providing positive data 0007 Accordingly, although bispecific antibody con most frequently demonstrating a small effect. The reality is structs have great therapeutic value in redirecting the body’s that therapeutic antibodies offer very modest clinical benefit own immune system to achieve the eradication or neutralisa in the area of oncology. Thus, there remains a demand for tion of unwanted cells, the activation of such redirection more effective immunotherapeutic agents. requires that it be tightly controlled so that the cytotoxic 0003 Bispecific antibodies unify two antigen binding potential is recruited and applied only in the direction sites of different specificity into a single construct giving intended. Thus, there is a strong need for further immuno them the ability to bring together two discrete antigens with therapeutic agents that overcome limitations described exquisite specificity. The first bispecific antibodies resembled above. natural immunoglobulin G (IgG) molecules in which the two 0008. The present inventors have now devised a means for arms were equipped with distinct binding specificities. The recruiting and activating immune cells (eg T cells) to target concept of using these bispecific antibodies to engage cyto unwanted cells, wherein the immune cells are only activated toxic T cells for cancer cell lysis was originally shown by when in the vicinity of the targeted cells. As will become Staerz and colleagues in 1985 (Nature 1985,314: 628). Since apparent below, such selective activation of immune cells is then, different kinds of constructs have been made and devel based on selective unmasking of an immune cell binding oped for the same purpose. Recent focus has been on creating region in the vicinity of unwanted target cells by an agent that antibody constructs by joining two single chain Fv regions resides in the vicinity of the unwanted cells. In this way, the (scFv antibody fragments) while omitting the Fc portion technology is more specific for the unwanted cell (eg more present in full immunoglobulins. Each Schv unit in Such con cancer specific) by virtue of the immune cell binding region structs (so-called bispecific T cell engagers or BiTE antibod only being unmasked in the vicinity of the unwanted cell (eg ies) is made up of one variable domain from each of the heavy in the presence of a cancer associated protease). This dramati (VH) and light (VL) antibody chains, joined with one another cally expands the therapeutic window of bispecificantibodies via a synthetic polypeptide linker. The resulting bispecific and so facilitates larger doses of drug to be given leading to single chain antibody is therefore a species containing two greater target effect. VH/VL pairs of different specificity on a single polypeptide 0009. Accordingly, a first aspect of the invention provides chain of approximately 55 kDa. a molecule comprising: (i) a targeting moiety capable of 0004 Promising experimental results have emerged from directly or indirectly targeting to unwanted cells, and (ii) a the use of BiTE antibodies. Kufer and colleagues have dem further moiety that has a masked immune cell binding region onstrated that CD3/target antigen-bispecificantibodies of this So as to prevent binding of the further moiety to an immune design have an exceptionally high potency, and can engage cell, wherein the masked immune cell binding region is CD8+ and CD4+ T cells for redirected lysis of cancer cells at capable of being selectively unmasked when the molecule is very low effector to target ratios (Mack, PNAS (1995), in the vicinity of the unwanted cells so as to allow binding of 92:7021-5).
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