An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer

Steven R. Leong; Wei-Ching Liang; Yan Wu; Lisa Crocker; Eric Cheng; Deepak Sampath; Rachana Ohri; Helga Raab; Philip E. Hass; Thinh  Pham; Ron Firestein; Dongwei Li; Melissa Schutten; Nicola J. Stagg; Annie Ogasawara; Neelima Koppada; Leslie Roth; Simon P. Williams; Byoung-Chul Lee; Cecile Chalouni; Ivan Peng; Jason DeVoss; Jarrod Tremayne; Paul Polakis; Andrew G. Polson

doi:10.1021/mp5007745

An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer

Steven R. Leong, Wei-Ching Liang, Yan Wu, Lisa Crocker, Eric Cheng, Deepak Sampath, Rachana Ohri, Helga Raab, Philip E. Hass, Thinh Pham, Ron Firestein, Dongwei Li, Melissa Schutten, Nicola J. Stagg, Annie Ogasawara, Neelima Koppada, Leslie Roth, Simon P. Williams, Byoung-Chul Lee, Cecile ChalouniIvan Peng, Jason DeVoss, Jarrod Tremayne, Paul Polakis, Andrew G. Polson

Research output: Contribution to journal › Article › Research › peer-review

34 Citations (Scopus)

Abstract

B7-H4 has been implicated in cancers of the female reproductive system and investigated for its possible use as a biomarker for cancer, but there are no preclinical studies to demonstrate that B7-H4 is a molecular target for therapeutic intervention of cancer. We provide evidence that the prevalence and expression levels of B7-H4 are high in different subtypes of breast cancer and that only a few normal tissues express B7-H4 on the cell membrane. These profiles of low normal expression and upregulation in cancer provide an opportunity for the use of antibody-drug conjugates (ADCs), cytotoxic drugs chemically linked to antibodies, for the treatment of B7-H4 positive cancers. We have developed an ADC specific to B7-H4 that uses a linker drug consisting of a potent antimitotic, monomethyl auristatin E (MMAE), linked to engineered cysteines (THIOMAB) via a protease labile linker. We will refer to ADCs that use the THIOMAB format as TDCs to help distinguish the format from standard MC-vc-MMAE ADCs that are conjugated to the interchain disulfide bonds. Anti-B7-H4 (h1D11)-MC-vc-PAB-MMAE (h1D11 TDC) produced durable tumor regression in cell line and patient-derived xenograft models of triple-negative breast cancer. It also binds rat B7-H4 with similar affinity to human and allowed us to test for target dependent toxicity in rats. We found that our anti-B7-H4 TDC has toxicity findings similar to untargeted TDC. Our results validate B7-H4 as an ADC target for breast cancer and support the possible use of this TDC in the treatment of B7-H4⁺ breast cancer.

Original language	English
Pages (from-to)	1717-1729
Number of pages	13
Journal	Molecular Pharmaceutics
Volume	12
Issue number	6
DOIs	https://doi.org/10.1021/mp5007745
Publication status	Published - Jun 2015
Externally published	Yes

Keywords

antibody drug conjugate
B7-H4
breast cancer
monomethyl auristatin E (MMAE)
preclinical validation

Access to Document

10.1021/mp5007745

Link to publication in Scopus

Cite this

Leong, S. R., Liang, W-C., Wu, Y., Crocker, L., Cheng, E., Sampath, D., Ohri, R., Raab, H., Hass, P. E., Pham, T., Firestein, R., Li, D., Schutten, M., Stagg, N. J., Ogasawara, A., Koppada, N., Roth, L., Williams, S. P., Lee, B-C., ... Polson, A. G. (2015). An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. Molecular Pharmaceutics, 12(6), 1717-1729. https://doi.org/10.1021/mp5007745

Leong, Steven R. ; Liang, Wei-Ching ; Wu, Yan ; Crocker, Lisa ; Cheng, Eric ; Sampath, Deepak ; Ohri, Rachana ; Raab, Helga ; Hass, Philip E. ; Pham, Thinh ; Firestein, Ron ; Li, Dongwei ; Schutten, Melissa ; Stagg, Nicola J. ; Ogasawara, Annie ; Koppada, Neelima ; Roth, Leslie ; Williams, Simon P. ; Lee, Byoung-Chul ; Chalouni, Cecile ; Peng, Ivan ; DeVoss, Jason ; Tremayne, Jarrod ; Polakis, Paul ; Polson, Andrew G. / An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. In: Molecular Pharmaceutics. 2015 ; Vol. 12, No. 6. pp. 1717-1729.

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title = "An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer",

abstract = "B7-H4 has been implicated in cancers of the female reproductive system and investigated for its possible use as a biomarker for cancer, but there are no preclinical studies to demonstrate that B7-H4 is a molecular target for therapeutic intervention of cancer. We provide evidence that the prevalence and expression levels of B7-H4 are high in different subtypes of breast cancer and that only a few normal tissues express B7-H4 on the cell membrane. These profiles of low normal expression and upregulation in cancer provide an opportunity for the use of antibody-drug conjugates (ADCs), cytotoxic drugs chemically linked to antibodies, for the treatment of B7-H4 positive cancers. We have developed an ADC specific to B7-H4 that uses a linker drug consisting of a potent antimitotic, monomethyl auristatin E (MMAE), linked to engineered cysteines (THIOMAB) via a protease labile linker. We will refer to ADCs that use the THIOMAB format as TDCs to help distinguish the format from standard MC-vc-MMAE ADCs that are conjugated to the interchain disulfide bonds. Anti-B7-H4 (h1D11)-MC-vc-PAB-MMAE (h1D11 TDC) produced durable tumor regression in cell line and patient-derived xenograft models of triple-negative breast cancer. It also binds rat B7-H4 with similar affinity to human and allowed us to test for target dependent toxicity in rats. We found that our anti-B7-H4 TDC has toxicity findings similar to untargeted TDC. Our results validate B7-H4 as an ADC target for breast cancer and support the possible use of this TDC in the treatment of B7-H4+ breast cancer.",

keywords = "antibody drug conjugate, B7-H4, breast cancer, monomethyl auristatin E (MMAE), preclinical validation",

author = "Leong, {Steven R.} and Wei-Ching Liang and Yan Wu and Lisa Crocker and Eric Cheng and Deepak Sampath and Rachana Ohri and Helga Raab and Hass, {Philip E.} and Thinh Pham and Ron Firestein and Dongwei Li and Melissa Schutten and Stagg, {Nicola J.} and Annie Ogasawara and Neelima Koppada and Leslie Roth and Williams, {Simon P.} and Byoung-Chul Lee and Cecile Chalouni and Ivan Peng and Jason DeVoss and Jarrod Tremayne and Paul Polakis and Polson, {Andrew G.}",

year = "2015",

month = jun,

doi = "10.1021/mp5007745",

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Leong, SR, Liang, W-C, Wu, Y, Crocker, L, Cheng, E, Sampath, D, Ohri, R, Raab, H, Hass, PE, Pham, T, Firestein, R, Li, D, Schutten, M, Stagg, NJ, Ogasawara, A, Koppada, N, Roth, L, Williams, SP, Lee, B-C, Chalouni, C, Peng, I, DeVoss, J, Tremayne, J, Polakis, P & Polson, AG 2015, 'An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer', Molecular Pharmaceutics, vol. 12, no. 6, pp. 1717-1729. https://doi.org/10.1021/mp5007745

An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer. / Leong, Steven R.; Liang, Wei-Ching; Wu, Yan; Crocker, Lisa; Cheng, Eric; Sampath, Deepak; Ohri, Rachana; Raab, Helga; Hass, Philip E.; Pham, Thinh ; Firestein, Ron; Li, Dongwei; Schutten, Melissa; Stagg, Nicola J.; Ogasawara, Annie; Koppada, Neelima; Roth, Leslie; Williams, Simon P.; Lee, Byoung-Chul; Chalouni, Cecile; Peng, Ivan; DeVoss, Jason; Tremayne, Jarrod; Polakis, Paul; Polson, Andrew G.

In: Molecular Pharmaceutics, Vol. 12, No. 6, 06.2015, p. 1717-1729.

Research output: Contribution to journal › Article › Research › peer-review

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AB - B7-H4 has been implicated in cancers of the female reproductive system and investigated for its possible use as a biomarker for cancer, but there are no preclinical studies to demonstrate that B7-H4 is a molecular target for therapeutic intervention of cancer. We provide evidence that the prevalence and expression levels of B7-H4 are high in different subtypes of breast cancer and that only a few normal tissues express B7-H4 on the cell membrane. These profiles of low normal expression and upregulation in cancer provide an opportunity for the use of antibody-drug conjugates (ADCs), cytotoxic drugs chemically linked to antibodies, for the treatment of B7-H4 positive cancers. We have developed an ADC specific to B7-H4 that uses a linker drug consisting of a potent antimitotic, monomethyl auristatin E (MMAE), linked to engineered cysteines (THIOMAB) via a protease labile linker. We will refer to ADCs that use the THIOMAB format as TDCs to help distinguish the format from standard MC-vc-MMAE ADCs that are conjugated to the interchain disulfide bonds. Anti-B7-H4 (h1D11)-MC-vc-PAB-MMAE (h1D11 TDC) produced durable tumor regression in cell line and patient-derived xenograft models of triple-negative breast cancer. It also binds rat B7-H4 with similar affinity to human and allowed us to test for target dependent toxicity in rats. We found that our anti-B7-H4 TDC has toxicity findings similar to untargeted TDC. Our results validate B7-H4 as an ADC target for breast cancer and support the possible use of this TDC in the treatment of B7-H4+ breast cancer.

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