Abstract 1197: Outstanding preclinical efficacy of a novel maytansinoid-antibody-drug conjugate targeting LAMP1 in patient-derived xenograft solid tumors

Abstract

Lysosome-associated membrane protein 1 (LAMP1) is involved in the maintenance of lysosome membrane integrity and phagolysosome formation. LAMP1 shows very limited expression at the cell surface in normal tissues while, a moderate to high expression was found in a number of solid tumors. We generated SAR428926, an antibody drug conjugate (ADC) comprising an anti-LAMP1 humanized monoclonal antibody conjugated via a cleavable SPDB linker, to the maytansinoid derivative DM4, a tubulin interfering molecule. Here we report the annotation of LAMP1 expression in a large panel of human tumors and correlate it to the in vivo efficacy of SAR428926 in a panel of over 50 human patient-derived xenograft (PDX) solid tumors. Indications of interest were identified by immunohistochemistry (IHC) conducted on a large panel of frozen tumor samples using the murine version of the therapeutic anti-human LAMP1 antibody. The prevalence of tumor samples with positive membrane staining was 49% in breast invasive lobular or ductal carcinoma, and in particular in a TNBC subset (87%), 25% in gastric adenocarcinoma, 52% in colon/rectum adenocarcinoma, 22% in lung adenocarcinoma, 20% in lung squamous cell carcinoma, 25% in prostate adenocarcinoma and 31% in ovary adenocarcinoma. In vivo efficacy of SAR428926 was evaluated in PDX models engrafted subcutaneously into immunocompromised SCID mice. PDX models retain the molecular diversity, cellular heterogeneity, and histology typically seen in patient tumors and offer a distinct advantage over cell line models. The PDX models used in the study, which include colon, breast, lung, prostate, gastric and ovarian cancer, were selected by IHC based on LAMP1 expression levels distribution and the frequency of LAMP1 membrane positive cells, which varied between 5% and 100% of the tumor cells, allowing coverage of a wide variety of cases. Outstanding efficacy with complete regressions was observed at 5 mg/kg iv single administration, a dose that gives an exposure tolerated in toxicology species. Efficacy was also observed at lower doses of 2.5 mg/kg and 1.25 mg/kg after single administration. Our results show that while the presence of the antigen is required as there is no efficacy in LAMP1-negative PDX, there is no linear correlation between the level of antigen expression and the antitumor activity across the panel of PDX tested. In addition to membrane LAMP1 expression, a key driver for efficacy was the intrinsic sensitivity of the PDX models to DM4. These results highlight the potential of ADCs that target human cancers expressing membrane LAMP1 at the surface of tumor cells. These encouraging preclinical data have prompted us to initiate IND-enabling studies with the goal to progress anti LAMP1-ADC to the clinic in patients with solid tumors expressing LAMP1 at the cell surface. The phase I study started in October 2015. Citation Format: Loreley Calvet, Anne-Marie Lefebvre, Celine Nicolazzi, Lydia Blot, Corinne Thomas, Yves Baudat, Beatrice Cameron, Carlos Garcia-Echeverria, Jean-Francois Mayaux, Veronique Blanc, Cecile Combeau, Souad Naimi, Sukhvinder Sidhu. Outstanding preclinical efficacy of a novel maytansinoid-antibody-drug conjugate targeting LAMP1 in patient-derived xenograft solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1197.

Immunotherapy for Breast Cancer Treatment

“…J. 25 (3): [140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156] experiments in late 2000 clearly showing that angiogenesis is not a central mechanism for the disseminated tumor cells or micrometastatic disease. Pertuzumab is a type of human monoclonal IgG antibody and has therapeutic confirmation in combination with trastuzumab for HER2-positive metastatic breast cancer patients [84] .…”

“…In normal cells, LAMP-1 is normally expressed in lysosomes, though it is transferred to the surface of tumor cells, where its expression level is associated with invasion and metastasis of different types of tumors [154] . SAR428926 is a LAMP1 ADC in which Ab-1 is connected to the [155,156] . Pcadherin has a major role in calcium-dependent cellcell adhesion.…”

“…J. 25 (3): 140- 156 141 Table 1. Histological typing of breast carcinomas [165] Non-invasive lobular neoplasia luminal B) [11,12] .…”

The target invites a foe: antibody–drug conjugates in gynecologic oncology

“…SAR428926 is an ADC constituting an anti-LAMP1 humanized monoclonal antibody conjugated via a cleavable linker to the maytansinoid derivative DM4. In-vivo efficacy of SAR428926 was demonstrated in a panel of over 50 human patient-derived xenograft models [41].…”

“…Although the presence of the antigen is required for SAR428926 to have activity (there is no efficacy in LAMP1-negative PDX models), there appears to be no linear correlation between the level of antigen expression and the antitumor activity across the panel of PDX tested [41].…”