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 | |
| Publication status | Published - Jun 2015 |
| Externally published | Yes |
Keywords
- antibody drug conjugate
- B7-H4
- breast cancer
- monomethyl auristatin E (MMAE)
- preclinical validation
Cite this
}
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
TY - JOUR
T1 - An Anti-B7-H4 antibody-drug conjugate for the treatment of breast cancer
AU - Leong, Steven R.
AU - Liang, Wei-Ching
AU - Wu, Yan
AU - Crocker, Lisa
AU - Cheng, Eric
AU - Sampath, Deepak
AU - Ohri, Rachana
AU - Raab, Helga
AU - Hass, Philip E.
AU - Pham, Thinh
AU - Firestein, Ron
AU - Li, Dongwei
AU - Schutten, Melissa
AU - Stagg, Nicola J.
AU - Ogasawara, Annie
AU - Koppada, Neelima
AU - Roth, Leslie
AU - Williams, Simon P.
AU - Lee, Byoung-Chul
AU - Chalouni, Cecile
AU - Peng, Ivan
AU - DeVoss, Jason
AU - Tremayne, Jarrod
AU - Polakis, Paul
AU - Polson, Andrew G.
PY - 2015/6
Y1 - 2015/6
N2 - 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.
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.
KW - antibody drug conjugate
KW - B7-H4
KW - breast cancer
KW - monomethyl auristatin E (MMAE)
KW - preclinical validation
UR - http://www.scopus.com/inward/record.url?scp=84930673864&partnerID=8YFLogxK
U2 - 10.1021/mp5007745
DO - 10.1021/mp5007745
M3 - Article
C2 - 25853436
AN - SCOPUS:84930673864
VL - 12
SP - 1717
EP - 1729
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 6
ER -