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.
authors: Steven R
authors: SR
authors: Leong
authors: Wei-Ching
authors: WC
authors: Liang
authors: Yan
authors: Y
authors: Wu
authors: Lisa
authors: L
authors: Crocker
authors: Eric
authors: E
authors: Cheng
authors: Deepak
authors: D
authors: Sampath
authors: Rachana
authors: R
authors: Ohri
authors: Helga
authors: H
authors: Raab
authors: Philip E
authors: PE
authors: Hass
authors: Thinh
authors: T
authors: Pham
authors: Ron
authors: R
authors: Firestein
authors: Dongwei
authors: D
authors: Li
authors: Melissa
authors: M
authors: Schutten
authors: Nicola J
authors: NJ
authors: Stagg
authors: Annie
authors: A
authors: Ogasawara
authors: Neelima
authors: N
authors: Koppada
authors: Leslie
authors: L
authors: Roth
authors: Simon P
authors: SP
authors: Williams
authors: Byoung-Chul
authors: BC
authors: Lee
authors: Cecile
authors: C
authors: Chalouni
authors: Ivan
authors: I
authors: Peng
authors: Jason
authors: J
authors: DeVoss
authors: Jarrod
authors: J
authors: Tremayne
authors: Paul
authors: P
authors: Polakis
authors: Andrew G
authors: AG
authors: Polson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; C495575:monomethyl auristatin E
keywords: B7-H4; antibody−drug conjugate; breast cancer; monomethyl auristatin E (MMAE); preclinical validation