Technology

Potential to provide fundamental breakthroughs in drug design

Precision engineering capabilities and expanded genetic code technology platform with broad applicability. By integrating these two methodologies, we have the unique potential to enhance the therapeutic functions of conventional biologics and bio-conjugates.

The Need for Enhanced Bio-conjugates

Bio-conjugates combine two or more biologically active components into a single drug, initially designed to expand the clinical benefit seen with biologics. While successful, leading treatments typically rely on cysteine and lysine for conjugation, which limits drug design in several ways:

  1. Conjugation chemistry is predetermined with limited room to optimize reactivity, stability and selectivity
  2. Location and number of these natural amino acids within the protein diminish the ability to control both the site and number of conjugations
  3. Creates a mixture of random, non-uniform and unoptimized drug conjugates that limits efficacy and introduces safety concerns

Enter Engineered Precision Biologics (EPBs):

The Ambrx solution designed to overcome challenges in traditional bio-conjugate drug development.

Engineered Precision Biologics

Leveraging our proprietary expanded genetic code technology platform, we are designing our EPBs to overcome inherent limitations of traditional bioconjugates to and create optimized molecules with improved safety and efficacy.

Our technology platform allows us to incorporate synthetic amino acids (SAAs) into proteins within living cells – both bacterial and mammalian. Incorporating the SAA in a site-specific manner creates a unique and predictable attachment point for our conjugations, allowing us to obtain over 90% homogeneity. This allows us to use a wide range of proprietary payloads and linkers for site-specific conjugation to achieve desired, potentially new, biological functions. Resulting therapeutic candidates can be manufactured in commercial-friendly bacterial and mammalian systems.

With the potential to take recombinant DNA technologies into new territories by improving and enabling the field of bio-conjugates, we believe our platform will serve as an innovation engine for our current programs and additional EPBs. These therapeutic programs will be developed by Ambrx or in collaboration with pharmaceutical companies.

We believe that our technology platform allows us to engineer a precisely optimized bio-conjugate by:

  1. Selecting the precise number of amino acids and conjugation positions in the protein
  2. Designing the conjugation chemistries
  3. Expanding the types of payloads that can be conjugated

Publications

Shastri P, Zhu J, Skidmore L, Liang X, Ji Y, Gu Y, Tian F, Yao S, Xia G., “Nonclinical Development of Next-generation Site-specific HER2-targeting Antibody-drug Conjugate (ARX788) for Breast Cancer Treatment.” Molecular Cancer Therapeutics,Sep 19(9):1822-1832, 2020.

Skidmore L, Sakamuri S, Knudsen NA, Hewet A, Milutinovic S, Barkho W, Biroc S, Kirtley J, Marsden R, Storey K, Lopez I, Yu W, Fang SY, Yao S, Gu Y, Tian F., “ARX788, a Site-specific Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers.” Molecular Cancer Therapeutics, Sep 19(9):1833-1843, 2020.

Barok M., Le Joncour V., Martins A., Isola J., Salmikangas M., Laakkonen P., Joensuu H. “ARX788, a novel anti-HER2 antibody drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer.” Cancer Letters, 7(473):156-163, 2020.

Hu, X., Zhang J., Ji D., Xiong G., Xia G., Ji Y., Liang X., Yao S., Tian F. “A Phase 1 Study of ARX788, a HER2-Targeting Antibody Drug Conjugate, in Patients with Metastatic HER2-Positive Breast Cancer.” San Antonio Breast Cancer Symposium, December 2019.

Humphreys, R., Kirtley, J., Hewet, A., Biroc, S., Knudsen, N., Zhang, X., Skidmore, L., Kiener, P., and Wahl, A. “Site-specific conjugation of ARX788, an Antibody Drug Conjugate (ADC) targeting HER2, generates a potent and stable targeted therapeutic for multiple cancers.” AACR Philadelphia, 2015.

Brandish, PE., Palmieri A., Antonenko S., Beaumont M., Benso L., Cancilla M., Cheng M., Firdos J., Garbaccio R., Garvin-Queen L., Gately D., Kern J., Knudsen N., 1, Ma H., Manibusan A., Shin JS., Stivers P., Sun Y., Tomazela D., Woo HC., Zaller D., Zhang S., Zhang Y., Zielstorff M., “Development of anti-CD74 antibody drug conjugates to target glucocorticoids to immune cells.” Bioconjug Chem, 29(7): 2357-2369, 2018.

Kern JC., Dooney D., Zhang R., Liang L., Brandish PE.., Cheng M, Feng G, Beck A., Bresson D, Firdos J., Gately D., Knudsen N., Manibusan A., Sun .Y, Garbaccio RM., “Novel phosphate modified cathepsin B linkers: improving aqueous solubility and enhancing payload scope of ADCs.” Bioconjug Chem, 27(9): 2081-2088, 2016.

Kern JC., Cancilla M., Dooney D., Kwasnjuk K., Zhang R., Beaumont M., Figueroa I., Hsieh S., Liang L., Tomazela D., Zhang J., Brandish PE., Palmieri A., Stivers P., Cheng M., Feng G., Geda P., Shah S., Beck A., Bresson D., Firdos J., Gately D., Knudsen N., Manibusan A., Schultz PG., Sun Y., Garbaccio RM., “Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates.” J. Am. Chem Soc, 1238(4): 1430-1445, 2016.

Tian F, Lu Y, Manibusan A, Sellers A, Tran H, Sun Y, Phuong T, Barnett R, Hehli B, Song F, Deguzman MJ, Ensari S, Pinkstaff JK, Sullivan LM, Biroc SL, Cho H, Schultz PG, Dijoseph J, Dougher M, Ma D, Dushin R, Leal M, Tchistiakova L, Feyfant E, Gerber HP, Sapra P. “A general approach to site-specific antibody drug conjugates.” Proc. Nat. Acad. Sci., 111(5):1766-71, 2014.

Jackson D1, Atkinson J1, Guevara CI1, Zhang C1, Kery V1, Moon SJ1, Virata C1, Yang P1, Lowe C1, Pinkstaff J2, Cho H2, Knudsen N2, Manibusan A2, Tian F2, Sun Y2, Lu Y2, Sellers A2, Jia XC1, Joseph I1, Anand B1, Morrison K1, Pereira DS1, Stover D1. “In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody-drug conjugates.” PLoS One, 9(1):e83865, 2014.

Axup, J.A., Bajjuri, K.M., Ritland, M., Hutchins, B.M., Kim, C., Kazane, S.A., Halder, R., Forsyth, J.S., Santidrian, A.F., Stafin, K., Liu, Y., Tran, H., Seller, A.J., Biroc, S.L., Szydlik, A., Pinkstaff, J.K., Tian, F., Sinha, S.C., Felding-Habermann, B., Smider, V.V., Schultz, P.G. “Synthesis of site-specific antibody-drug conjugates using unnatural amino acids.” Proc. Nat. Acad. Sci., 109(40):16101-16106, 2012.

Alexandra Flemming, Nature Reviews Drug Discovery 13, 178-178 doi:10.1038/nrd4266
Kularatne SA1, Deshmukh V, Ma J, Tardif V, Lim RK, Pugh HM, Sun Y, Manibusan A, Sellers AJ, Barnett RS, Srinagesh S, Forsyth JS, Hassenpflug W, Tian F, Javahishvili T, Felding-Habermann B, Lawson BR, Kazane SA, Schultz PG. “A CXCR4-Targeted Site-Specific Antibody-Drug Conjugate.” Angew Chem Int Ed Engl. 2014 Sep 11. doi: 10.1002/anie.201408103.

Bispecifics

Cao Y, Axup JY., Ma JS., Wang RE., Choi S., Tardif V., Lim RK., Pugh HM., Lawson BR., Welzel G., Kazane SA., Sun Y., Tian F., Srinagesh S., Javahishvili T., Schultz PG., Kim CH., “Multiformat T-cell-engaging bispecific antibodies targeting human breast cancers.” Angew Chem Int Ed Engl, 54(24): 7022-7077, 2015.

Kim, C., Axup, J.Y., Lawson, B., Yun, H., Tardif, V., Choi, S., Zhou, Q., Dubrovska, A., Biroc, S.L., Marsden, R., Pinkstaff, J., Smider, V.V., Schultz, P.G., “A bispecific small molecule antibody conjugate targeting prostate cancer.” Proc Natl Acad Sci USA, 110(44):17796-801, 2013.

Müller TD, Sullivan LM, Habegger K, Yi CX, Kabra D, Grant E, Ottaway N, Krishna R, Holland J, Hembree J, Perez-Tilve D, Pfluger PT, DeGuzman MJ, Siladi ME, Kraynov VS, Axelrod DW, DiMarchi R, Pinkstaff JK, Tschöp MH. “Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21.” J. Pept. Sci., 18(6):383-93, 2012.

Mu J, Pinkstaff J, Li Z, Skidmore L, Li N, Myler H, Dallas-Yang Q, Putnam AM, Yao J, Bussell S, Wu M, Norman TC, Rodriguez CG, Kimmel B, Metzger JM, Manibusan A, Lee D, Zaller DM, Zhang BB, DiMarchi RD, Berger JP, Axelrod DW. “FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents.” Diabetes, 61(2):505-12, 2012.

Kang, M., Lu, Y., Chen, S., Tian, F. “Harnessing the power of an expanded genetic code toward next-generation biopharmaceuticals.” Curr Opin Chem Biol, 46: 123-129, 2018.

Javahishvili T, Manibusan A, Srinagesh S, Lee D, Ensari S, Shimazu M, Schultz PG. “Role of tRNA Orthogonality in an Expanded Genetic Code.” ACS Chem Biol., Epub, 2014.

Xie, J., Schultz, P.G. “A chemical toolkit for proteins – an expanded genetic code.” Nat. Rev. Mol. Cell Biol., 7(10):775-82,2006.
Kim, C., Axup, J., Schultz, P.G., “Protein conjugation with genetically encoded unnatural amino acids,” Curr Opin Chem Biol, 17(3):412-9, 2013.

Cho, H.S., Daniel, T., Buechler, Y.J., Litzinger, D.C., Maio, Z., Putnam, A-M. H., Kraynov, V., Sim, B-C., Bussell, S., Javahishvilli, T., Kaphle, S., Viramontes, G., Ong, M., Chu, S., GC, B., Lieu, R., Knudsen, N., Castiglioni, P., Norman, T., Axelrod, D.W., Hoffman, A.R., Schultz, P.G., DiMarchi, R., Kimmel, B.E. “Optimized clinical performance of growth hormone with an expanded genetic code.” Proc. Nat. Acad. Sci., 108(22):9060-5, 2011.

Clemmensen C, Chabenne J, Finan B, Sullivan L, Fischer K, Küchler D, Sehrer L, Ograjsek T, Hofmann S, Schriever SS, Pfluger PT, Pinkstaff J, Tschöp MH, Dimarchi R, Müller TD. “GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet.” Diabetes Epub, 2013.

Lu, H., Wang. D., Kazane, S.A., Javahishvili, T., Tian, F., Song, F., Sellers, A., Barnett, B., Schultz, P.G., “Site-specific antibody-polymer conjugates for SiRNA delivery.” J Am Chem Soc, 135(37):13885-91, 2013.

Additional Applications

Kazane, S.A., Sok, D., Uson, M.L., Cho, E.H., Kuhn, P., Schultz, P.G., Smider, V.V. “Site-specific DNA-antibody conjugates for specific and sensitive immuno-PCR.” Proc. Nat. Acad. Sci., 109(10):3731-6, 2012.

Intellectual Property

Ambrx strives to protect our product candidates and our core technology platforms through a variety of methods, including seeking and maintaining patents intended to cover our products and compositions, their methods of use and processes for their manufacture, our platform technologies and any other inventions that are commercially important to the development of our business.

We have entered into exclusive license agreements with various academic and research institutions to obtain the rights to use certain patents for the development and commercialization of our product candidates. We also rely on know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position. We seek to obtain domestic and international patent protection and endeavor to promptly file patent applications for new commercially valuable inventions to expand our intellectual property portfolio.

Our intellectual property portfolio is currently composed of issued US patents and pending US patent applications that we own. We also control, through exclusive licenses from academic and research institutions, issued US patents and pending US patent applications. This portfolio covers our core technology platforms and other technologies, such as our linker chemistry technology.

We own 12 families of U.S. and foreign patents and patent applications covering our platforms, including over 25 issued US Patents relating to the essential components of our platform systems and methods of manufacturing the polypeptides that comprise a non-naturally encoded amino acid.

We also have an exclusive license to a portfolio consisting of three families of issued patents and pending patent applications co-owned by The Scripps Research Institute and The Regents of the University of California, Berkeley. Through this exclusive license, we currently have exclusive rights to 28 issued U.S. patents and 138 issued foreign patents relating to methods and reagents for making proteins containing non-natively encoded amino acids.