Patrys

Deoxymabs

Deoxymab 3E10

3e103E10 is a lupus auto antibody that penetrates live cell nuclei by binding to DNA or its precursors outside of cells and then following it into cell nuclei through a nucleoside transporter. Once in the nucleus 3E10 interferes with DNA repair processes, but the degree of inhibition of DNA repair caused by 3E10 is modest and is not enough to kill a normal cell that has robust mechanisms to manage insults to DNA. On the other hand, many cancer cells are exquisitely sensitive to DNA damage because their DNA repair machinery is already impaired. When these cancer cells encounter 3E10, they accumulate more DNA damage than they can handle and ultimately die. 3E10 is therefore selectively toxic to cancer cells that have deficiencies in DNA repair, which includes a wide range of malignancies such as gliomas, melanomas, prostate, breast, and ovarian cancers and many others. When combined with DNA-damaging agents such as chemotherapy or radiation, 3E10 has an even greater effect on these cancer cells.

3E10 is particularly well suited for use in cancer therapy because it preferentially localizes to tumors but not normal tissues. As tumors grow and go through cycles of proliferation they are constantly releasing DNA, and this results in accumulation of a “cloud” of DNA in the tumor vicinity. 3E10 is specifically attracted to DNA, and moreover is dependent on the presence of extracellular DNA in order to penetrate cell nuclei. The cloud of DNA in the tumor vicinity therefore not only attracts 3E10 to the area, but then also facilitates nuclear penetration by 3E10 into the tumor cell nuclei where it then inhibits DNA repair and kills the tumor cells and sensitizes them to DNA-damaging agents.

To prepare 3E10 for clinical trial testing, it will be modified to remove any components that could carry a risk of causing lupus-like side effects. In addition, 3E10 will be optimised to enhance its binding to DNA and increase its effect on DNA repair-deficient cancer cells. 3E10 is currently in preclinical development.

Deoxymab 5C6

5C6 is another lupus autoantibody that penetrates live cell nuclei, similar to 3E10 is highly toxic to cancer cells with DNA repair deficiencies and has similar potential to be used in cancer therapy.

Publications

3E10 Deoxymab

Chen Z, Patel JM, Noble PW, Garcia C, Hong Z, Hansen JE, Zhou J. A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors. Oncotarget 2016 Aug 2 doi: 10.18632/oncotarget.11015. [Epub ahead of print]

Noble PW, Bernatsky S, Clarke AE, Isenberg DA, Ramsey-Goldman R, Hansen JE. DNA-damaging autoantibodies and cancer: the lupus butterfly theory. Nature Reviews Rheumatology. 2016 12(7): 429-34.

Weisbart RH, Chan G, Jordaan G, Noble PW, Liu Y, Glazer PM, Nishimura RN, Hansen JE. DNA-dependent targeting of cell nuclei by a lupus autoantibody. Sci Rep 2015 5: 12022.

Noble PW, Chan G, Young MR, Weisbart RH, Hansen JE. Optimizing a lupus autoantibody for targeted cancer therapy. Cancer Res  2015 75(11): 2285-91.

Hansen JE, Chan G, Liu Y, Hegan DC, Dalal S, Dray E, Kwon Y, Xu Y, Xu X, Peterson-Roth E, Geiger E, Liu Y, Gera J, Sweasy JB, Sung P, Rockwell S, Nishimura RN, Weisbart RH, Glazer PM. Targeting cancer with a lupus autoantibody. Sci Transl Med. 2012 4(157): 157ra142.

Hansen JE, Tse CM, Chan G, Heinze ER, Nishimura RN, Weisbart RH. Intranuclear protein transduction through a nucleoside salvage pathway. J Biol Chem 2007 282(29): 20790-3.

Spertini F, Leimgruber A, Morel B, Khazaeli MB, Yamamoto K. Dayer JM, Weisbart RH, Lee ML. J Rheumatol 1999 26(12): 2602-8.

Weisbart RH, Stempniak M, Harris S, Zack DJ, Ferreri K. An autoantibody is modified for use as a delivery system to target the cell nucleus: therapeutic implications. J Autoimmun 1998 11(5): 539-46.

Zack DJ, Stempniak M, Wong AL, Taylor C, Weisbart RH. Mechanisms of cellular penetration and nuclear localization of an anti-double strand DNA autoantibody. J Immunol 1996 157(5): 2082-8.

Weisbart RH, Noritake DT, Wong AL, Chan G, Kacena A, Colburn KK. A conserved anti-DNA antibody idiotype associated with nephritis in murine and human systemic lupus erythematosus. J Immunol 1990 144(7): 2653-8.

5C6 Deoxymab

Noble PW, Young MR, Weisbart RH, Hansen JE. A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells. Sci Rep 2014 4: 5958. Doi: 10.1038/srep05958.