An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: Case study of TENB2

C. Andrew Boswell, Eduardo E. Mundo, Ron Firestein, Crystal Zhang, Weiguang Mao, Herman S. Gill, Cynthia Young, Nina Ljumanovic, Shannon Stainton, Sheila Ulufatu, Aimee Fourie-O'Donohue, Katherine R. Kozak, Reina Fuji, Paul Polakis, Leslie A. Khawli, Kedan Lin

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Abstract

Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues.

Original languageEnglish
Pages (from-to)445-457
Number of pages13
JournalBritish Journal of Pharmacology
Volume168
Issue number2
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

Keywords

  • antibody-drug conjugates
  • ELISA
  • indium-111-DOTA
  • prostate cancer
  • TENB2
  • tissue distribution

Cite this

Boswell, C. Andrew ; Mundo, Eduardo E. ; Firestein, Ron ; Zhang, Crystal ; Mao, Weiguang ; Gill, Herman S. ; Young, Cynthia ; Ljumanovic, Nina ; Stainton, Shannon ; Ulufatu, Sheila ; Fourie-O'Donohue, Aimee ; Kozak, Katherine R. ; Fuji, Reina ; Polakis, Paul ; Khawli, Leslie A. ; Lin, Kedan. / An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates : Case study of TENB2. In: British Journal of Pharmacology. 2013 ; Vol. 168, No. 2. pp. 445-457.
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title = "An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: Case study of TENB2",
abstract = "Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues.",
keywords = "antibody-drug conjugates, ELISA, indium-111-DOTA, prostate cancer, TENB2, tissue distribution",
author = "Boswell, {C. Andrew} and Mundo, {Eduardo E.} and Ron Firestein and Crystal Zhang and Weiguang Mao and Gill, {Herman S.} and Cynthia Young and Nina Ljumanovic and Shannon Stainton and Sheila Ulufatu and Aimee Fourie-O'Donohue and Kozak, {Katherine R.} and Reina Fuji and Paul Polakis and Khawli, {Leslie A.} and Kedan Lin",
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Boswell, CA, Mundo, EE, Firestein, R, Zhang, C, Mao, W, Gill, HS, Young, C, Ljumanovic, N, Stainton, S, Ulufatu, S, Fourie-O'Donohue, A, Kozak, KR, Fuji, R, Polakis, P, Khawli, LA & Lin, K 2013, 'An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: Case study of TENB2', British Journal of Pharmacology, vol. 168, no. 2, pp. 445-457. https://doi.org/10.1111/j.1476-5381.2012.02138.x

An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates : Case study of TENB2. / Boswell, C. Andrew; Mundo, Eduardo E.; Firestein, Ron; Zhang, Crystal; Mao, Weiguang; Gill, Herman S.; Young, Cynthia; Ljumanovic, Nina; Stainton, Shannon; Ulufatu, Sheila; Fourie-O'Donohue, Aimee; Kozak, Katherine R.; Fuji, Reina; Polakis, Paul; Khawli, Leslie A.; Lin, Kedan.

In: British Journal of Pharmacology, Vol. 168, No. 2, 01.2013, p. 445-457.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates

T2 - Case study of TENB2

AU - Boswell, C. Andrew

AU - Mundo, Eduardo E.

AU - Firestein, Ron

AU - Zhang, Crystal

AU - Mao, Weiguang

AU - Gill, Herman S.

AU - Young, Cynthia

AU - Ljumanovic, Nina

AU - Stainton, Shannon

AU - Ulufatu, Sheila

AU - Fourie-O'Donohue, Aimee

AU - Kozak, Katherine R.

AU - Fuji, Reina

AU - Polakis, Paul

AU - Khawli, Leslie A.

AU - Lin, Kedan

PY - 2013/1

Y1 - 2013/1

N2 - Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues.

AB - Background and Purpose The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental Approach A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. Key Results The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and Implications Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues.

KW - antibody-drug conjugates

KW - ELISA

KW - indium-111-DOTA

KW - prostate cancer

KW - TENB2

KW - tissue distribution

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