Jose F. Ponte

Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models

Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC. Combinations of IMGN853 with carboplatin or doxorubicin resulted in synergistic antiproliferative effects in the IGROV-1 ovarian cancer cell line in vitro. IMGN853 potentiated the cytotoxic activity of carboplatin via growth arrest and augmented DNA damage; cell cycle perturbations were also observed in cells treated with the IMGN853/doxorubicin combination. These benefits translated into improved antitumor activity in patient-derived xenograft models in vivo in both the platinum-sensitive (IMGN853/carboplatin) and platinum-resistant (IMGN853/pegylated liposomal doxorubicin) settings. IMGN853 co-treatment also improved the in vivo efficacy of bevacizumab in platinum-resistant EOC models, with combination regimens causing significant regressions and complete responses in the majority of tumor-bearing mice. Histological analysis of OV-90 ovarian xenograft tumors revealed that concurrent administration of IMGN853 and bevacizumab caused rapid disruption of tumor microvasculature and extensive necrosis, underscoring the superior bioactivity profile of the combination regimen. Overall, these demonstrations of combinatorial benefit conferred by the addition of the first FRα-targeting ADC to established therapies provide a compelling framework for the potential application of IMGN853 in the treatment of patients with advanced ovarian cancer.

Phase 1 dose‐escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α‐targeting antibody‐drug conjugate, in patients with solid tumors

Mirvetuximab soravtansine (IMGN853) is an antibody‐drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose‐escalation study, the authors investigated IMGN853 in patients with FRα‐positive solid tumors.

A new, triglycyl peptide linker for antibody-drug conjugates (ADCs) with improved targeted killing of cancer cells

A triglycyl peptide linker (CX) was designed for use in antibody–drug conjugates (ADC), aiming to provide efficient release and lysosomal efflux of cytotoxic catabolites within targeted cancer cells. ADCs comprising anti-epithelial cell adhesion molecule (anti-EpCAM) and anti-EGFR antibodies with maytansinoid payloads were prepared using CX or a noncleavable SMCC linker (CX and SMCC ADCs). The in vitro cytotoxic activities of CX and SMCC ADCs were similar for several cancer cell lines; however, the CX ADC was more active (5–100-fold lower IC50) than the SMCC ADC in other cell lines, including a multidrug-resistant line. Both CX and SMCC ADCs showed comparable MTDs and pharmacokinetics in CD-1 mice. In Calu-3 tumor xenografts, antitumor efficacy was observed with the anti-EpCAM CX ADC at a 5-fold lower dose than the corresponding SMCC ADC in vivo. Similarly, the anti-EGFR CX ADC showed improved antitumor activity over the respective SMCC conjugate in HSC-2 and H1975 tumor models; however, both exhibited similar activity against FaDu xenografts. Mechanistically, in contrast with the charged lysine-linked catabolite of SMCC ADC, a significant fraction of the carboxylic acid catabolite of CX ADC could be uncharged in the acidic lysosomes, and thus diffuse out readily into the cytosol. Upon release from tumor cells, CX catabolites are charged at extracellular pH and do not penetrate and kill neighboring cells, similar to the SMCC catabolite. Overall, these data suggest that CX represents a promising linker option for the development of ADCs with improved therapeutic properties. Mol Cancer Ther; 15(6); 1311–20. ©2016 AACR.

The Antitumor Activity of IMGN529, a CD37-Targeting Antibody-Drug Conjugate, Is Potentiated by Rituximab in Non-Hodgkin Lymphoma Models

Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways. The strongest enhancement in potency was seen with anti-CD20 antibodies, including rituximab. The combination of IMGN529 and rituximab was more potent than either agent alone, and this combinatorial benefit was associated with increased apoptotic induction and cell death. Additional studies revealed that rituximab treatment increased the internalization and degradation of the CD37-targeting antibody moiety of IMGN529. The combination of IMGN529 and rituximab was highly efficacious in multiple xenograft models, with superior antitumor efficacy seen compared to either agent alone or treatment with R-CHOP therapy. These findings suggest a novel mechanism whereby the potency of IMGN529 can be enhanced by CD20 binding, which results in the increased internalization and degradation of IMGN529 leading to the generation of greater amounts of cytotoxic catabolite. Overall, these data provide a biological rationale for the enhanced activity of IMGN529 in combination with rituximab and support the ongoing clinical evaluation of IMGN529 in combination with rituximab in patients with relapsed and/or refractory DLBCL.

Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing.

Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such conjugates were prepared utilizing different dipeptides in the linkage including Gly-Gly, l-Val-l-Cit, and all four stereoisomers of the Ala-Ala dipeptide. The properties of AaMCs could be altered by the choice of dipeptide in the linker. Each of the AaMCs, except the AaMC bearing a d-Ala-d-Ala peptide linker, displayed more bystander killing in vitro than maytansinoid ADCs that utilize disulfide linkers. In mouse models, the anti-CanAg AaMC bearing a d-Ala-l-Ala dipeptide in the linker was shown to be more efficacious against heterogeneous HT-29 xenografts than maytansinoid ADCs that utilize disulfide linkers, while both types of the conjugates displayed similar tolerabilities.

Abstract 5483: Preclinical evaluation of IMGN289, an anti-EGFR antibody-maytansinoid conjugate for the treatment of squamous cell carcinoma of the head and neck.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Squamous cell carcinoma of the head and neck (SCCHN) include cancers that affect the squamous epithelium of the mouth, larynx, nasal passages, sinuses and pharynx. The epidermal growth factor receptor (EGFR) has emerged as an important antigen for novel targeted therapies in SCCHN, where EGFR overexpression correlates with aggressive disease, resistance to standard therapies and a poor prognosis. EGFR expression was evaluated on a panel of SCCHN xenografts and primary SCCHN tumors using a calibrated immunohistochemical (IHC) staining method on formalin-fixed paraffin-embedded sections. The results demonstrated that 83 of 85 (98%) SCCHN tumors stained positive for EGFR and, of the 83 positive tumors, 80 (96%) had high EGFR expression, confirming that EGFR represents an attractive therapeutic target for SCCHN. IMGN289 is an antibody-“drug” conjugate (ADC) consisting of the humanized monoclonal antibody, J2898A, which selectively binds to EGFR, linked to the potent cytotoxic maytansinoid, DM1, via a SMCC thioether linker. The cytotoxic activity of IMGN289 was evaluated against a panel of SCCHN cell lines in vitro. IMGN289 was active in 9 of 13 cell lines assayed, including 5 of 8 that were resistant to cetuximab. Cytotoxic activity was observed against cell lines originating from multiple anatomic sites including the pharynx, oral cavity, larynx and tongue. The anti-tumor activity of IMGN289 was evaluated in EGFR-positive SCCHN xenograft models with expression levels comparable to patient tumors. Immunodeficient mice bearing established subcutaneous xenograft tumors were treated with a single intravenous injection of IMGN289 at 1, 2.5 or 5.0 mg/kg (based on antibody concentration). A group of mice dosed with the J2898A antibody at 5 mg/kg was included in the study. In the FaDu xenograft model, IMGN289 was active with a minimally efficacious dose (MED) of 1 mg/kg, highly active at 2.5, and at 5 mg/kg 5/6 partial regressions (PR) and 2/6 complete regressions (CR) were observed. Conjugation of DM1 to J2898A achieved greater anti-tumor activity than J2898A, which was active in the study but without regressions. In the HSC-2 xenograft model, IMGN289 was also highly active, with a MED of 2.5 mg/kg and tumor regression at 5 mg/kg with 6/6 PR and 4/6 CR. Once again, the activity of IMGN289 was more robust than naked J2898A antibody, which was active with 2/6 PR and 1/6 CR. The strong anti-tumor activity of IMGN289 against SCCHN xenograft tumors with EGFR expression levels comparable to patient tumors suggests that IMGN289 may be a promising compound for the treatment of SCCHN. Citation Format: Jose F. Ponte, Yulius Y. Setiady, Ling Dong, Anna Skaletskaya, Christina N. Carrigan, Alfred Anderson-Villaluz, Robert J. Lutz, Jan Pinkas. Preclinical evaluation of IMGN289, an anti-EGFR antibody-maytansinoid conjugate for the treatment of squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5483. doi:10.1158/1538-7445.AM2013-5483

Abstract 5463: Development of a novel antibody-maytansinoid conjugate, IMGN289, for the treatment of EGFR-expressing solid tumors.

EGFR is an attractive target for the treatment of a variety of solid tumors because of its role as a driver oncogene and high level of expression. Four EGFR-targeting agents, including two antibodies (Abs), have been approved for clinical use. Despite anti-tumor benefits, inhibition of EGFR pathway is associated with significant dermatologic toxicities; resistance to EGFR antagonists also develops. To enhance potency with comparable or better tolerability, we developed IMGN289, an EGFR-targeting antibody-“drug” conjugate (ADC) that disrupts tumor growth both by inhibiting EGFR signaling and through direct anti-mitotic activity. To reduce potential dermatologic toxicities associated with EGFR pathway inhibition, a unique Ab discovery approach was employed. Hybridomas from mice immunized with EGFR-expressing tumor cells were screened for EGFR binding and selective inhibitory activity against EGFR-dependent tumor cells. This approach revealed a novel class of Ab with selective EGFR antagonistic activity. A humanized lead Ab was identified, J2898A, which was comparable in potency to cetuximab in vitro against a panel of EGFR-dependent tumor cell lines and in vivo against two head and neck tumor xenograft models. Notably, in cultures of human primary keratinocytes, this Ab was markedly less cytotoxic than cetuximab and did not affect TNFα-induced cytokine production, which has been implicated in chronic dermatologic toxicities induced by other anti-EGFR agents. To further enhance cytotoxic activity and to potentially overcome resistance to EGFR-targeting therapies, J2898A was conjugated to the maytansinoid DM1, a potent anti-tubulin agent, via a non-cleavable linker, SMCC. IMGN289 was not only more potent than J2898A against EGFR-dependent tumors, but also was effective against EGFR-positive tumor cells that grow independently of signaling via the EGFR pathway or have acquired resistance to EGFR inhibitors, including lung adenocarcinoma cell lines harboring the T790M EGFR mutation or MET gene amplification. Despite having potent activity against EGFR-expressing tumor cells, IMGN289 was less toxic to cultured keratinocytes than cetuximab. Moreover, a toxicology study in cynomolgus monkeys demonstrated that IMGN289 was well tolerated and exhibited a similar toxicity profile to that published for trastuzumab emtansine (T-DM1), another ADC which utilizes SMCC-DM1 as the selected linker-payload format. In summary, IMGN289 combines EGFR inhibition mediated by its J2898A Ab component with the potent cytotoxicity provided by its DM1 payload, and is highly active against EGFR-positive tumors regardless of their dependency on the EGFR pathway. IMGN289 thus represents a promising novel candidate for treatment of EGFR-expressing solid tumors. Citation Format: Yulius Y. Setiady, Peter U. Park, Jose F. Ponte, Ling Dong, Anna Skaletskaya, Jennifer A. Coccia, Erica Hong, Lauren Clancy, Lingyun Rui, Jan Pinkas, Robert J. Lutz, John M. Lambert, Thomas D. Chittenden. Development of a novel antibody-maytansinoid conjugate, IMGN289, for the treatment of EGFR-expressing solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5463. doi:10.1158/1538-7445.AM2013-5463

A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer

Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody-drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansines mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease. Ongoing Phase III monotherapy and Phase Ib/II combination trials evaluating its activity in the setting of platinum resistance are emphasized, which will help define its role in the evolving landscape of ovarian cancer therapy.

Abstract C170: Preclinical evaluation of mirvetuximab soravtansine (IMGN853) combination therapy in ovarian cancer xenograft models

Background: IMGN853 is a folate receptor α (FRα)-binding antibody-drug conjugate (ADC) that utilizes the potent tubulin-targeting maytansinoid, DM4, as its cytotoxic agent. FRα is highly expressed in many solid tumors, particularly epithelial ovarian cancer (EOC), endometrial cancer and non-small cell lung adenocarcinoma. IMGN853 is currently being evaluated as monotherapy in FRα-positive solid tumors in a Phase 1 trial (NCT01609556), with encouraging results recently reported in 17 evaluable patients treated at 6.0 mg/kg adjusted ideal body weight (AIBW) with platinum-resistant EOC (Moore K et al, 2015). Methods: EOC cell line xenograft models plus EOC patient derived xenograft (PDX) models that had FRα expression representative of patients enrolled in the Phase 1 trial were used to assess IMGN853 single agent and combination therapy activity. Anti-cancer therapies used in EOC were assessed. Results from studies with bevacizumab (Bev), carboplatin and pegylated liposomal doxorubicin (PLD) are reported herein. Results: IMGN853 plus Bev was assessed in multiple models including OV90 and IGROV-1 EOC cell line xenografts and a platinum-resistant EOC PDX model, and was consistently more active than either agent alone. In most studies, monotherapy IMGN853 or Bev was active with few partial or complete regressions. In contrast, combination IMGN853 + Bev was highly active, with a majority of the animals having partial or complete tumor regression. The combination activity was substantially more than additive and studies to understand the mechanism(s) responsible for the enhanced activity are ongoing. Combination carboplatin + IMGN853 was more active than carboplatin + paclitaxel in OV90 EOC xenografts. The addition of Bev to carboplatin + paclitaxel enhanced activity compared to carboplatin + paclitaxel. Carboplatin + IMGN853 was more efficacious than the triple combination of carboplatin + paclitaxel + Bev. Carboplatin + IMGN853 + Bev was the most active combination with all mice having tumors that completely regressed. Finally, the combination of PLD and IMGN853 was highly active in a platinum-resistant EOC PDX model, and much more active than PLD or IMGN853 alone. All combinations with IMGN853 described above were well tolerated. Conclusion: Combination therapy efficacy of IMGN853 with Bev was substantially more than additive in multiple models of platinum resistant EOC. Combination IMGN853 + PLD is more efficacious than either monotherapy and combination IMGN853 + carboplatin is more efficacious than carboplatin + paclitaxel in the models studied. Addition of Bev to the carboplatin + IMGN853 combination further enhanced activity. Studies to understand the mechanism(s) responsible for the enhanced combination activity are under way. The efficacy observed in these models suggests that IMGN853 in combination with PLD, or Bev and/or carboplatin may be promising regimens to evaluate in clinical trials of EOC both in the relapsed and upfront settings. A phase1b clinical study assessing doublet combinations of IMGN853 with PLD, Bev and carboplatin in relapsed EOC is planned for 2015. Citation Format: Jose F. Ponte, Jennifer Coccia, Leanne Lanieri, Rabih Gabriel, Jan Pinkas, Rodrigo Ruiz-Soto. Preclinical evaluation of mirvetuximab soravtansine (IMGN853) combination therapy in ovarian cancer xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C170.

Abstract 5467: IMGN289, an EGFR-targeting antibody-maytansinoid conjugate with potent activity against non-small cell lung cancer (NSCLC) regardless of dependency on EGFR pathway.

NSCLC accounts for approximately 85% of all lung cancers. Based on tumor histology, NSCLC can be subdivided into adenocarcinoma (AC), squamous cell carcinoma (SCC), and large cell carcinoma (LCC), which account for 40%, 25-30% and 10-15% of NSCLC cases, respectively. In a fraction of AC cases, driver oncogenes have been identified that enable effective treatment with targeted therapies. For most NSCLC cases, however, etiology is still unknown and effective targeted therapies have yet to be achieved. Additionally, even cancers that initially respond to targeted therapies eventually develop resistance, creating the need for other therapeutic approaches. EGFR is one of the best characterized driver oncogenes in NSCLC and also is frequently expressed at high levels in this indication. In house immunohistochemical analysis found EGFR to be highly expressed in 23.8% of AC (n = 21), 60% of SCC (n = 10) and 50% of LCC (n = 8), confirming published data that EGFR represents an attractive therapeutic target for NSCLC. As a novel approach to targeting EGFR-expressing tumors, we have developed IMGN289, an antibody-“drug” conjugate (ADC) consisting of the J2898A antibody (Ab), which selectively binds to EGFR and inhibits EGFR-driven tumor cell growth, conjugated to the maytansinoid DM1, a potent anti-microtubule agent, via the SMCC thioether linker. IMGN289 showed significantly enhanced cytotoxic activity, relative to cetuximab or unconjugated J2898A, against a panel of NSCLC cell lines dependent on EGFR signaling. In vitro, anti-EGFR Abs typically inhibit less than 70% of tumor cell growth at 30 nM concentration, whereas IMGN289 exposure approached 100% inhibition at a significantly lower concentration. Enhanced potency of IMGN289 against EGFR-dependent tumors was demonstrated in vivo in the H292 xenograft tumor model, where the minimally effective doses of IMGN289 and its J2898A Ab were 1 and 3 mg/kg, respectively. In addition, IMGN289 was effective against EGFR-expressing NSCLC cells that are not dependent on EGFR signaling and therefore resistant to anti-EGFR Abs. For example, IMGN289 was active against H226 and H1703 mesenchymal cell lines in vitro and H1703 xenograft tumor in vivo, while neither cetuximab nor J2898A alone was active. IMGN289 was also active against EGFR mutant HCC827 cell lines that have acquired resistance to EGFR tyrosine kinase inhibitors through T790M EGFR mutation or MET gene amplification. Thus, EGFR-targeting IMGN289 achieves a distinct anti-tumor mechanism that is independent of EGFR pathway inhibition. In summary, IMGN289 is highly active against EGFR-positive NSCLC cells regardless of dependency on the EGFR pathway and represents a promising therapeutic candidate for NSCLC. Citation Format: Thomas D. Chittenden, Yulius Y. Setiady, Peter U. Park, Jose F. Ponte, Ling Dong, Anna Skaletskaya, Christina N. Carrigan, Alfred A. Villaluz, Jan Pinkas, Robert J. Lutz, John M. Lambert. IMGN289, an EGFR-targeting antibody-maytansinoid conjugate with potent activity against non-small cell lung cancer (NSCLC) regardless of dependency on EGFR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5467. doi:10.1158/1538-7445.AM2013-5467