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(12) Patent Application Publication (10) Pub. No.: US 2011/0033378 A1 Dimasi Et Al US 2011 0033378A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0033378 A1 Dimasi et al. (43) Pub. Date: Feb. 10, 2011 (54) CYSTEINE ENGINEERED ANTIBODIES FOR Related U.S. Application Data SITE-SPECIFIC CONUGATION (60) Provisional application No. 61/022,073, filed on Jan. 18, 2008. (75) Inventors: Nazzareno Dimasi, Gaithersburg, O O MD (US); Changshou Gao Publication Classification Potomac, MD (US); Herren Wu, (51) Int. Cl. Boyds, MD (US) A6II 5L/It (2006.01) C07K 6/00 (2006.01) Correspondence Address: YK i.By 30.8 MEDIMMUNE LLC Patrick Scott Alban9 CI2N 5/10 (2006.01) CI2N 9/96 (2006.01) ONE MEDIMMUNE WAY C07K 9/00 (2006.01) GAITHERSBURG, MD 20878 (US) A 6LX 39/395 (2006.01) A6IP35/00 (2006.01) (73) Assignee: Medlmmune, LLC., Gaithersburg, A6IP37/02 (2006.01) MD (US) A6IP 29/00 (2006.01) A6IP3L/00 (2006.01) (21) Appl. No.: 12/863,322 (52) U.S. Cl. .................. 424/1.49; 530/387.3; 536/23.53; 435/320.1; 435/325; 435/188: 530/391.5; 530/391.9; 424/133.1; 424/1811; 424/179.1 (22) PCT Filed: Jan. 16, 2009 (57) ABSTRACT (86). PCT No.: PCT/USO9/31294 Cysteine engineered antibodies useful for the site-specific conjugation to a variety of agents are provided. Methods for S371 (c)(1), the design, preparation, screening, selection and use of Such (2), (4) Date: Sep. 9, 2010 antibodies are also provided. Patent Application Publication Feb. 10, 2011 Sheet 1 of 23 US 2011/0033378A1 v?eun61) Patent Application Publication Feb. 10, 2011 Sheet 2 of 23 US 2011/0033378A1 •*** ?.einfil£ Patent Application Publication Feb. 10, 2011 Sheet 3 of 23 US 2011/0033378A1 Swa wir ce wit ess Y. W is it (xèpuln=3)1961JoyLCL); OLeun61– r rei r re re-i irr 3. N in y v N Cri d - d an isd is3 is is .5 is. N.. Y tal r) is ) N. Y ess a 4 0. O C S3 92. 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CROSS-REFERENCE TO RELATED majority of the cancer cells. APPLICATIONS 0006 With respect to chemotherapy, there are a variety of 0001. This application claims benefit of U.S. provisional chemotherapeutic agents available for treatment of cancer. A application No. 61/022,073, filed Jan. 18, 2008, which is significant majority of cancer chemotherapeutics act by incorporated by reference in its entirety. inhibiting DNA synthesis (see, for example, Gilman et al., Goodman and Gilman's: The Pharmacological Basis of 2. FIELD OF THE INVENTION Therapeutics, Eighth Ed. (Pergamon Press, New York, 0002 The invention relates to antibodies comprising cys 1990)). As such, chemotherapy agents are inherently nonspe teine engineered CH1 domains which result in free thiol cific. In addition almost all chemotherapeutic agents are groups for conjugation reactions. Also provided are methods toxic, and chemotherapy causes significant, and often dan gerous, side effects, including severe nausea, bone marrow of design, modification, production, and use of such antibod depression, immunosuppression, etc. (see, for example, 1CS Stockdale, 1998, “Principles Of Cancer Patient Manage 3. BACKGROUND OF THE INVENTION ment” in Scientific American Medicine, Vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10). Furthermore, even with 3.1 Cancer and Cancer Therapies administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the 0003 More than 1.2 million Americans develop cancer chemotherapeutic agents. each year. Cancer is the second leading case of death in the United States and if current trends continue, cancer is 0007 Cancer therapy can now also involve biological expected to be the leading cause of the death by the year 2010. therapy or immunotherapy. Biological therapies/immuno Lung and prostate cancer are the top cancer killers for men in therapies are limited in number and although more specific the United States. Lung and breast cancer are the top cancer then chemotherapeutic agents many still target both health killers for women in the United States. One in two men in the and cancerous cells. In addition, such therapies may produce United States will be diagnosed with cancer at some time side effects such as rashes or Swellings, flu-like symptoms, during his lifetime. One in three women in the United States including fever, chills and fatigue, digestive tract problems or will be diagnosed with cancer at Some time during her life allergic reactions. time. Current treatment options, such as Surgery, chemo therapy and radiation treatment, are often either ineffective or 3.2 Antibodies for the Treatment of Cancer present serious side effects. 0004 One barrier to the development of anti-metastasis 0008 Antibodies are immunological proteins that bind a agents has been the assay systems that are used to design and specific antigen. In most mammals, including humans and evaluate these drugs. Most conventional cancer therapies tar mice, antibodies are constructed from paired heavy and light get rapidly growing cells. However, cancer cells do not nec polypeptide chains. Each chain is made up of two distinct essarily grow more rapidly but instead Survive and grow regions, referred to as the variable (Fv) and constant (Fc) under conditions that are non-permissive to normal cells regions. The light and heavy chain Fv regions contain the (Lawrence and Steeg, 1996, World J. Urol. 14:124-130). antigenbinding determinants of the molecule and are respon These fundamental differences between the behaviors of nor sible for binding the target antigen. The Fc regions define the mal and malignant cells provide opportunities for therapeutic class (or isotype) of antibody (IgG for example) and are targeting. The paradigm that micrometastatic tumors have responsible for binding a number of natural proteins to elicit already disseminated throughout the body emphasizes the important biochemical events. need to evaluate potential chemotherapeutic drugs in the con 0009. The Fc region of an antibody interacts with a num text of a foreign and three-dimensional microenvironment. ber of ligands including Fc receptors and other ligands, Many standard cancer drug assays measure tumor cell growth imparting an array of important functional capabilities or Survival under typical cell culture conditions (i.e., mono referred to as effector functions. An important family of Fc layer growth). However, cell behavior in two-dimensional receptors for the IgG class are the Fc gamma receptors assays often does not reliably predict tumor cell behavior in (FcyRs). These receptors mediate communication between V1VO. antibodies and the cellular arm of the immune system 0005. Currently, cancer therapy may involve surgery, che (Raghavanet al., 1996, Annu Rev Cell Dev Biol 12:181-220; motherapy, hormonal therapy and/or radiation treatment to Ravetch et al., 2001, Annu Rev Immunol 19:275-290). In eradicate neoplastic cells in a patient (see, for example, humans this protein family includes FcyRI (CID64), includ Stockdale, 1998, “Principles of Cancer Patient Manage ing isoforms FcyRIA, FcyRIB, and FcyRIC; FcyRII (CD32), ment, in Scientific American: Medicine, Vol.
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