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Scientist Profile

Paul J. Carter

Senior Director, Antibody Engineering
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"The long duration of drug development relative to the span of a career reminds me that, like the renown landscape gardener, Lancelot "Capability" Brown, one needs to plant for future generations."
 

I first joined Genentech as a Postdoctoral Fellow in 1986 and left as a Senior Scientist and Head of the Postdoctoral Program in 2000. I then rejoined Genentech in 2010 as a Senior Director and Staff Scientist to lead the Antibody Engineering.

My most significant contributions to drug development include initiating the antibody humanization program at Genentech and co-inventing Herceptin® (trastuzumab), a humanized antibody approved by the FDA for the treatment of HER2-overexpressing breast cancer. I am a co-inventor of three other antibodies that have reached at least early clinical development.

Beyond antibody therapeutics, my laboratory has developed technologies for high-level antibody Fab fragment expression that were subsequently utilized for production of the anti-VEGF Fab, Lucentis® (ranibizumab injection). We also developed "knobs-in-holes" technology for creating bispecific human IgG and other bifunctional molecules. This technology was enabling for MetMAb, a monovalent anti-Met antibody currently in phase II clinical trials.

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My Focus

My research interests focus on creating future generations of antibody therapeutics by rational design and molecular evolution approaches. My prime motivator is the desire to generate antibodies that provide greater benefit to patients than achieved with current antibody drugs.

Improving the clinical potential of antibodies seems feasible given the growing repertoire of antibody optimization technologies. For example, one can potentially overcome biophysical, functional and immunogenic limitations of antibodies, enhance existing properties as well as endow these molecules with novel activities. Growing knowledge of the mechanisms of action and mechanisms of resistance of antibody drugs are anticipated to guide the design of next generation antibodies.

Commercial impetus to improve antibody performance is provided by the need to differentiate one self from others. Competition will surely intensify as many approved and investigational drugs target the same antigen and/or diseases.

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Publications & Recognition
  • Therapeutic antibodies for autoimmunity and inflammation.
  • Nat Rev Immunol 2010 May; 10(5): 301-16.
  • Chan AC, Carter PJ.
  • View Abstract on PubMed
  • Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas.
  • Blood 2009 Apr 30; 113(18): 4352-61.
  • Gerber HP, Kung-Sutherland M, Stone I, Morris-Tilden C, Miyamoto J, McCormick R, Alley SC, Okeley N, Hayes B, Hernandez-Ilizaliturri FJ, McDonagh CF, Carter PJ, Benjamin D, Grewal IS.
  • View Abstract on PubMed
  • Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index.
  • Mol Cancer Ther 2008 Sep; 7(9): 2913-23.
  • McDonagh CF, Kim KM, Turcott E, Brown LL, Westendorf L, Feist T, Sussman D, Stone I, Anderson M, Miyamoto J, Lyon R, Alley SC, Gerber HP, Carter PJ.
  • View Abstract on PubMed
 
View All Publications & Recognition
 
  • Medical Research Council Laboratory of Molecular Biology, University of Cambridge, U.K.
  • Ph.D.
  • 1982-1986
  • University of Cambridge, U.K.
  • B.A. in Natural Sciences
  • 1979-1982
Publications & Recognition
  • Therapeutic antibodies for autoimmunity and inflammation.
  • Nat Rev Immunol 2010 May; 10(5): 301-16.
  • Chan AC, Carter PJ.
  • View Abstract on PubMed
  • Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas.
  • Blood 2009 Apr 30; 113(18): 4352-61.
  • Gerber HP, Kung-Sutherland M, Stone I, Morris-Tilden C, Miyamoto J, McCormick R, Alley SC, Okeley N, Hayes B, Hernandez-Ilizaliturri FJ, McDonagh CF, Carter PJ, Benjamin D, Grewal IS.
  • View Abstract on PubMed
  • Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index.
  • Mol Cancer Ther 2008 Sep; 7(9): 2913-23.
  • McDonagh CF, Kim KM, Turcott E, Brown LL, Westendorf L, Feist T, Sussman D, Stone I, Anderson M, Miyamoto J, Lyon R, Alley SC, Gerber HP, Carter PJ.
  • View Abstract on PubMed
  • Anti-CD30 diabody-drug conjugates with potent antitumor activity.
  • Mol Cancer Ther 2008 Aug; 7(8): 2486-97.
  • Kim KM, McDonagh CF, Westendorf L, Brown LL, Sussman D, Feist T, Lyon R, Alley SC, Okeley NM, Zhang X, Thompson MC, Stone I, Gerber HP, Carter PJ.
  • View Abstract on PubMed
  • D133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers.
  • Br J Cancer 2008 Jul 8; 99(1): 100-9.
  • Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, Zabinski RF, Sutherland MK, Gerber HP, Van Orden KL, Moore PA, Ruben SM, Carter PJ.
  • View Abstract on PubMed
  • Antibody-drug conjugates for cancer therapy.
  • Cancer J 2008 May-Jun; 14(3): 154-69.
  • Carter PJ, Senter PD.
  • View Abstract on PubMed
  • Antibody targeting of B-cell maturation antigen on malignant plasma cells.
  • Mol Cancer Ther 2007 Nov; 6(11): 3009-18.
  • Ryan MC, Hering M, Peckham D, McDonagh CF, Brown L, Kim KM, Meyer DL, Zabinski RF, Grewal IS, Carter PJ.
  • View Abstract on PubMed
  • Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97.
  • Mol Cancer Ther 2006 Jun; 5(6): 1474-82.
  • Smith LM, Nesterova A, Alley SC, Torgov MY, Carter PJ.
  • View Abstract on PubMed
  • Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment.
  • Protein Eng Des Sel 2006 Jul; 19(7): 299-307.
  • McDonagh CF, Turcott E, Westendorf L, Webster JB, Alley SC, Kim K, Andreyka J, Stone I, Hamblett KJ, Francisco JA, Carter P.
  • View Abstract on PubMed
  • Potent antibody therapeutics by design.
  • Nat Rev Immunol 2006 May; 6(5): 343-57.
  • Carter PJ.
  • View Abstract on PubMed
  • Identification and validation of cell surface antigens for antibody targeting in oncology.
  • Endocr Relat Cancer 2004 Dec; 11(4): 659-87.
  • Carter P, Smith L, Ryan M.
  • View Abstract on PubMed
  • Identification of potent human anti-IL-1RI antagonist antibodies.
  • Protein Eng Des Sel 2004 Jan; 17(1): 95-106.
  • Fredericks ZL, Forte C, Capuano IV, Zhou H, Vanden Bos T, Carter P. Identification of potent human anti-IL-1RI antagonist antibodies. Protein Eng Des Sel 2004 Jan; 17(1): 95-106.Fredericks ZL, Forte C, Capuano IV, Zhou H, Vanden Bos T, Carter P.
  • View Abstract on PubMed
  • Tech.Sight. Phage display. Affinity selection from biological libraries.
  • Science 2002 Oct 18; 298(5593): 621-2.
  • Smothers JF, Henikoff S, Carter P.
  • View Abstract on PubMed
  • Sequence plasticity in the antigen-binding site of a therapeutic anti-HER2 antibody.
  • J Mol Biol 2002 Aug 30; 321(5): 851-62.
  • Gerstner RB, Carter P, Lowman HB.
  • View Abstract on PubMed
  • Improving the efficacy of antibody-based cancer therapies.
  • Nat Rev Cancer 2001 Nov; 1(2): 118-29.
  • Carter P.
  • View Abstract on PubMed
  • Identification of a human anti-CD55 single-chain Fv by subtractive panning of a phage library using tumor and nontumor cell lines.
  • Cancer Res 1999 Jun 1; 59(11): 2718-23.
  • Ridgway JB, Ng E, Kern JA, Lee J, Brush J, Goddard A, Carter P.
  • View Abstract on PubMed
  • An efficient route to human bispecific IgG.
  • Nat Biotechnol 1998 Jul; 16(7): 677-81.
  • Merchant AM, Zhu Z, Yuan JQ, Goddard A, Adams CW, Presta LG, Carter P.
  • View Abstract on PubMed
  • Contribution of domain interface residues to the stability of antibody CH3 domain homodimers.
  • Biochemistry 1998 Jun 30; 37(26): 9266-73.
  • Dall'Acqua W, Simon AL, Mulkerrin MG, Carter P.
  • View Abstract on PubMed
  • Remodeling domain interfaces to enhance heterodimer formation.
  • Protein Sci 1997 Apr; 6(4): 781-8.
  • Zhu Z, Presta LG, Zapata G, Carter P.
  • View Abstract on PubMed
  • Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library.
  • J Mol Biol 1997 Jul 4; 270(1): 26-35.
  • Atwell S, Ridgway JB, Wells JA, Carter P.
  • View Abstract on PubMed
  • 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization.
  • Protein Eng 1996 Jul; 9(7): 617-21.
  • Ridgway JB, Presta LG, Carter P.
  • View Abstract on PubMed
  • High level secretion of a humanized bispecific diabody from Escherichia coli.
  • Biotechnology (N Y) 1996 Feb; 14(2): 192-6.
  • Zhu Z, Zapata G, Shalaby R, Snedecor B, Chen H, Carter P.
  • View Abstract on PubMed
  • Development of anti-p185HER2 immunoliposomes for cancer therapy.
  • Proc Natl Acad Sci USA 1995 Feb 28; 92(5): 1327-31.
  • Park JW, Hong K, Carter P, Asgari H, Guo LY, Keller GA, Wirth C, Shalaby R, Kotts C, Wood WI, et al.
  • View Abstract on PubMed
  • Development of a humanized disulfide-stabilized anti-p185HER2 Fv-beta-lactamase fusion protein for activation of a cephalosporin doxorubicin prodrug.
  • Cancer Res 1995 Jan 1; 55(1): 63-70.
  • Rodrigues ML, Presta LG, Kotts CE, Wirth C, Mordenti J, Osaka G, Wong WL, Nuijens A, Blackburn B, Carter P.
  • View Abstract on PubMed
  • Engineering Fab' fragments for efficient F(ab)2 formation in Escherichia coli and for improved in vivo stability.
  • J Immunol 1993 Dec 15; 151(12): 6954-61.
  • Rodrigues ML, Snedecor B, Chen C, Wong WL, Garg S, Blank GS, Maneval D, Carter P.
  • View Abstract on PubMed
  • X-ray structures of the antigen-binding domains from three variants of humanized anti-p185HER2 antibody 4D5 and comparison with molecular modeling.
  • J Mol Biol 1993 Feb 20; 229(4): 969-95.
  • Eigenbrot C, Randal M, Presta L, Carter P, Kossiakoff AA.
  • View Abstract on PubMed
  • Humanization of an anti-p185HER2 antibody for human cancer therapy.
  • Proc Natl Acad Sci USA 1992 May 15; 89(10): 4285-9.
  • Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM.
  • View Abstract on PubMed
  • High level Escherichia coli expression and production of a bivalent humanized antibody fragment.
  • Biotechnology (NY) 1992 Feb; 10(2): 163-7.
  • Carter P, Kelley RF, Rodrigues ML, Snedecor B, Covarrubias M, Velligan MD, Wong WL, Rowland AM, Kotts CE, Carver ME, et al.
  • View Abstract on PubMed
  • Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene.
  • J Exp Med 1992 Jan 1; 175(1): 217-25.
  • Shalaby MR, Shepard HM, Presta L, Rodrigues ML, Beverley PC, Feldmann M, Carter P.
  • View Abstract on PubMed
  • Probing the mechanism and improving the rate of substrate-assisted catalysis in subtilisin BPN'.
  • Biochemistry 1991 Jun 25; 30(25): 6142-8.
  • Carter P, Abrahmsén L, Wells JA.
  • View Abstract on PubMed
  • Functional interaction among catalytic residues in subtilisin BPN'.
  • Proteins 1990; 7(4): 335-42.
  • Carter P, Wells JA.
  • View Abstract on PubMed
  • Engineering subtilisin BPN' for site-specific proteolysis.
  • Proteins 1989; 6(3): 240-8.
  • Carter P, Nilsson B, Burnier JP, Burdick D, Wells JA.
  • View Abstract on PubMed
  • Dissecting the catalytic triad of a serine protease.
  • Nature 1988 Apr 7; 332(6164): 564-8.
  • Carter P, Wells JA.
  • View Abstract on PubMed
  • Engineering enzyme specificity by "substrate-assisted catalysis".
  • Science 1987 Jul 24; 237(4813): 394-9.
  • Carter P, Wells JA.
  • View Abstract on PubMed
  • Construction of heterodimer tyrosyl-tRNA synthetase shows tRNATyr interacts with both subunits.
  • Proc Natl Acad Sci USA 1986 Mar; 83(5): 1189-92.
  • Carter P, Bedouelle H, Winter G.
  • View Abstract on PubMed
  • Hydrogen bonding and biological specificity analysed by protein engineering.
  • Nature 1985 Mar 21-27; 314(6008): 235-8.
  • Fersht AR, Shi JP, Knill-Jones J, Lowe DM, Wilkinson AJ, Blow DM, Brick P, Carter P, Waye MM, Winter G.
  • View Abstract on PubMed
  • The use of double mutants to detect structural changes in the active site of the tyrosyl-tRNA synthetase (Bacillus stearothermophilus).
  • Cell 1984 Oct; 38(3): 835-40.
  • Carter PJ, Winter G, Wilkinson AJ, Fersht AR.
  • View Abstract on PubMed
  • A large increase in enzyme-substrate affinity by protein engineering.
  • Nature 1984 Jan 12-18; 307(5947): 187-8.
  • Wilkinson AJ, Fersht AR, Blow DM, Carter P, Winter G.
  • View Abstract on PubMed
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Awards & Honors
  • Research Fellowship
    Gonville and Caius College, University of Cambridge, U.K.
    1986
  • Max Perutz Student Prize, Medical Research Council Laboratory of Molecular Biology
    University of Cambridge, U.K.
    1985
  • Senior Scholarship
    Gonville and Caius College, University of Cambridge, U.K.
    1981
  • Scholarship
    Gonville and Caius College, University of Cambridge, U.K.
    1980
  • Entrance Exhibition
    Gonville and Caius College, University of Cambridge, U.K.
    1978
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Ellen Filvaroff, Senior Scientist and Alex Avardo, Receipent of Free Medicine From the Genentech® Access to Care Foundation, on the cover of Genentech's 2006 Annual Report.