On November 14, ImmunoGen announced that FDA has granted accelerated approval for its folate receptor alpha (FRα) antibody-drug conjugate mirvetuximab soravtansine (Elahere) for adult patients with FRα-positive platinum-resistant  epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have undergone one to three prior systemic treatment regimens.

Resistance to platinum-based chemotherapy is a major clinical challenge in ovarian cancer. FRα is a member of the folate receptor family that binds to folates with high affinity, resulting in their endocytic uptake into cells. Previous studies have shown that FRα is highly expressed in 76-89% of epithelial ovarian cancers and 35-68% of triple negative breast cancers, making FRα a drug target of interest. Moreover, FRα-mediated signaling pathways are capable of affecting tumor cell division and migration, so inhibition of FRα may also yield some degree of direct anticancer activity.

Mirvetuximab soravtansine is a first-in-class FRα ADC consisting of an FRα-targeting antibody, a cleavable linker  (sulfo-SPDB) and a potent tubulin-targeting agent (maytansinoid payload DM4). Each antibody molecule is conjugated to an average of three to four molecules of DM4, which acts as a potent antimitotic agent through its ability to inhibit microtubule dynamics.

Figure. Structure of Mirvetuximab soravtansine, source: https://www.immunogen.com/

Mirvetuximab soravtansine binds highly affinity to FRα expressed on the surface of tumor cells, prompting internalization of the ADC/receptor complex via antigen-mediated endocytosis. Lysosomal processing releases active DM4 catabolites - these maytansinoid derivatives inhibit tubulin polymerization and microtubule assembly, inducing potent antimitotic effects that lead to cell cycle arrest and apoptosis. The active metabolites may also spread to neighboring cells and induce further cell death (called "bystander killing").

Figure.  Mirvetuximab soravtansine mechanism of action, source: reference [2]

This FDA approval is based on the results of the pivotal Phase III SORAYA study. The study is an interventional, open-label, single-arm phase III clinical trial enrolling 106 patients designed to evaluate the efficacy and safety of mirvetuximab soravtansine in the treatment of patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who previously received one to three systemic therapies (at least 1 of which was bevacizumab). The primary endpoint was confirmed ORR as assessed by investigator and the key secondary endpoint was DOR. 

Mirvetuximab soravtansine demonstrated an ORR by investigator of 31.7% (95% confidence interval [CI]: 22.9, 41.6), including five complete responses (CRs). This included a complete response rate of 4.8% and a partial response rate of 26.9%. The median DOR was 6.9 months (95% CI: 5.6, 9.7) as assessed by investigator. 

ADCs in Development of ImmunoGen

Except for ELAHERE, ImmunoGen has another 3 ADCs in development in clinical and early stage pipelines, including IMGN151, Pivekimab Sunirine (IMGC632), IMGC936.

Figure. ImmunoGen pipeline, source: https://www.immunogen.com/

Pivekimab Sunirine (IMGN632)

IMGN632 is a CD123-targeted ADC for the treatment of hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN) and acute myeloid leukemia (AML).

IMGN632 uses a novel indolinobenzodiazepine (IGN) payload, DGN549, which alkylates DNA without cross-linking, resulting in single-stranded DNA breaks. The antibody uses a sub-nMol class high affinity humanized lgG1 antibody G4723, and a non-cleavable peptide linker conjugated by site-specific CYSMAB technology.

Figure. Structure of Pivekimab Sunirine (IMGN632), source: https://www.immunogen.com/

IMGN632 is currently in two clinical studies, a single-arm pivotal clinical phase 2 (CADENZA) study of monotherapy for BPDCN and a clinical phase 1 study (TRIAL 802) in combination with Vidaza and Venclexta for first-line R/R AML treatment. The FDA granted IMGN632 Breakthrough Therapy Designation in relapsed/refractory BPDCN.

IMGN151

IMGN151 is a next-generation anti-FRα product candidate designed to expand the indication to a wider range of tumor types with low FRα expression, such as ovarian cancer, NSCLC, TNBC and endometrial cancer. The IMGN151 is innovative in design, with an antibody that uses asymmetric, bivalent, biparatopic antibodies targeting two independent epitopes of FRα, allowing for better binding and internalization of the drug, coupling to the next generation of highly potent maytansinoid derivative DM21, via a stable tripeptide cleavable linker with higher hydrophobicity. IMGN151 has enhanced stability, longer half-life, and increased bystander activity. The average drug per antibody ratio is 3.5.

Figure. Structure of IMGN151, source: https://www.immunogen.com/

An IND has been filed for IMGN151 and previous preclinical studies have shown that the binary antibody used in IMGN151 promotes increased binding and internalization efficiency.

IMGC936

IMGC936 is a first-in-class ADAM9-targeting ADC being co-developed by Immunogen and MacroGenics. It is comprised of a high-affinity humanized antibody with YTE mutation for enhanced exposure through improved recycling, site-specifically conjugated to DM21, a next-generation maytansinoid microtubule-disrupting payload, via a tri-peptide cleavable linker.

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Figure. Structure of IMGC936, source: https://www.immunogen.com/

ADAM9 is a cell surface protein belonging to the ADAM (catabolic and metalloproteinase) family of proteases that has been implicated in cytokine and growth factor shedding and cell migration. Dysregulation of ADAM9 has been implicated in tumor progression and metastasis, as well as pathological neovascularization. ADAM9 is overexpressed in several solid tumor types (e.g., non-small cell lung cancer, gastric cancer, pancreatic cancer, triple-negative breast cancer and colorectal cancer) and is overexpressed in normal tissues with minimal expression, making ADAM9 an attractive target for ADC development.

IMGC936 has progressed to clinical phase I and is targeted for the treatment of advanced solid tumors, including NSCLC, TNBC, CRC, gastroesophageal cancer or pancreatic cancer.

References:
[1] https://investor.immunogen.com/news-releases/news-release-details/immunogen-announces-fda-accelerated-approval-elaheretm
[2] FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer, Kathleen N Moore, Ignace Vergote, Ana Oaknin, Nicoletta Colombo, Susana Banerjee, Amit Oza, Patricia Pautier, Karim Malek, and Michael J Birrer, Future Oncology 2018 14:17, 1669-1678

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