On February 27, 2019 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that 11 posters highlighting continued innovation in the field of ADCs will be presented at the upcoming American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting to be held March 29 – April 3, 2019 in Atlanta, Georgia (Press release, ImmunoGen, FEB 27, 2019, View Source [SID1234533737]).
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"ImmunoGen remains at the forefront of ADC innovation and the data to be presented at AACR (Free AACR Whitepaper) further demonstrate the value of our productive research platform," said Richard Gregory, Ph.D., ImmunoGen’s chief scientific officer.
The schedule of ImmunoGen’s presentations at AACR (Free AACR Whitepaper) is as follows:
IGN Payload Innovation
Title: Antibody-drug conjugates (ADCs) of a new class of N-10 amino linked DNA alkylating indolino-benzodiazepines (IGNs) – abstract #224
Date: March 31, 2019
Time: 1:00-5:00 PM ET
In an ongoing effort to further explore the structure-activity relationship of DNA alkylating effector molecules for ADCs, a new class of IGNs has been developed that possesses a self-immolative peptide linker attached at the N-10 amine of the imine-reduced IGN monomer subunit. ADCs with this class of payload displayed potent, antigen-specific in vitro activity across a panel of folate receptor α (FRα)-expressing cell lines.
Title: Antibody-drug conjugates (ADCs) with indolinobenzodiazepine dimer (IGN) payloads: DNA-binding mechanism of IGN catabolites in target cancer cells – abstract #1886
Date: March 31, 2019
Time: 1:00-5:00 PM ET
Investigation of the mechanism of binding of IGN catabolites with DNA in target cancer cells and with model duplex DNA or hairpin oligonucleotides. Both mono-and-di-imine IGN molecules remained bound to genomic DNA even at two days, suggesting a potent interaction with cellular DNA.
Advancement in Platform Linkers and Payloads
Title: Optimizing lysosomal activation of antibody-drug conjugates (ADCs) by incorporation of novel cleavable dipeptide linkers – abstract #0231
Date: March 31, 2019
Time: 1:00-5:00 PM ET
Based on screens of a panel of dipeptide linkers for efficient lysosomal proteolysis, several novel, previously unreported peptide linker designs were identified and incorporated into ADCs bearing a DNA-alkylating IGN payload. Several dipeptide linker designs were superior in rates of lysosomal processing compared to a reference standard L-Ala-L-Ala dipeptide linker.
Title: LC-MS based catabolite identification study of an ADC with DM21-C, a novel maytansinoid linker-payload – abstract #538
Date: March 31, 2019
Time: 1:00-5:00 PM ET
ImmunoGen’s newest ADC design uses the novel maytansinoid linker-payload, DM21-C that bears a peptidase/protease-cleavable linker. The goal of this study was to identify the catabolites generated upon incubation in antigen-positive cancer cells (both cell pellet and media), in mouse plasma, as well as in in vitro catabolic systems. DM51 (the thiol- resulting from self-immolation of the cleaved linker-payload) was identified as a major catabolite of the DM21-C ADC.
Title: Preclinical evaluation of DM21, a next‐generation maytansinoid payload with a stable peptide linker – abstract #3898
Date: April 2, 2019
Time: 1:00-5:00 PM ET
To evaluate the toxicity of DM21 as an ADC, it was conjugated to the non‐targeting, chimeric anti‐soybean trypsin inhibitor antibody (chKTI), and administered to cynomolgus monkeys in two groups with separate dose levels. chKTI‐DM21 was well-tolerated at both doses.
Novel Approaches to ADC Development
Title: Generation of site-specific DARPin drug conjugates using EGFR as a model system – abstract #215
Date: March 31, 2019
Time: 1:00-5:00 PM ET
DARPin molecules are small engineered proteins, derived from natural ankyrin repeat proteins that are selected to bind to specific targets with high affinity. DARPin drug conjugates (DDCs) were developed using a model EGFR multi-specific DARPin molecule, consisting of four DARPin domains linked together. Biophysical characterization showed the DDCs to be well behaved in stability and solubility assays.
Title: Development of a Probody-Drug Conjugate (PDC) targeting EpCAM for the treatment of solid tumors- abstract #1439
Date: March 31, 2019
Time: 1:00-5:00 PM ET
EpCAM is an attractive target for ADC development due to its overexpression on a variety of tumors of epithelial origin; however, EpCAM is also expressed on a variety of normal epithelia, thus limiting its utility as an ADC target due to potential toxicity. We aim to overcome this limitation by developing an EpCAM-targeting Probody drug conjugate (PDC). EpCAM-targeting PDCs were better tolerated than the corresponding EpCAM-targeting ADC even at higher dose levels and displayed longer half-lives and greater exposure.
Title: IMGC936, a first-in-class ADAM9-targeting antibody-drug conjugate, demonstrates promising anti-tumor activity – abstract #5136
Date: April 1, 2019
Time: 8:00 AM-12:00 PM ET
Under a co-development agreement with MacroGenics, it has been shown that ADAM9 is overexpressed in multiple solid tumor indications and that anti-ADAM9 antibodies are efficiently internalized and degraded by tumor cell lines, making ADAM9 an attractive target for ADC development. IMGC936 is the first ADAM9-targeting ADC to enter preclinical development. In vitro studies have demonstrated targeted cytotoxicity of IMGC936 across a panel of ADAM9-positve tumor cell lines with activity at least 2 logs greater than a non-targeting conjugate. Consistent with the activity observed in vitro, an anti-ADAM9-DM21 conjugate displayed compelling anti-tumor activity in multiple xenograft models representing non-small cell lung, gastric and colorectal cancers.
Title: Preclinical evaluation of a new, non-agonist ADC targeting MET-amplified tumors with a peptide-linked maytansinoid – abstract #4817
Date: April 3, 2019
Time: 8:00 AM-12:00 PM ET
cMet is an attractive target for ADCs, which may address the unmet treatment need for patients with tumors harboring MET amplification. To assess potential toxicity due to normal tissue expression, binding of our antibody to normal hepatocytes from humans and cynos was measured. Very low expression and binding versus tumor cell lines were found and demonstrated that the cytotoxic activity of disulfide-cleavable maytansinoid ADCs prepared from the hinge-variant cMet antibody was equivalent to the parental form in in vivo models. These data merit further exploration of this ADC as a novel treatment option for patients with MET-amplified tumors.
Optimizing ADC Dosing
Title: The potential benefit of lower drug-antibody ratio (DAR) on antibody-maytansinoid conjugate in vivo efficacy – abstract #219
Date: March 31, 2019
Time: 1:00-5:00 PM
Describes development of a cross-reactive model system that utilizes a chimeric anti-murine FRα antibody that binds with similar affinity to mouse and human FRα. Using this cross-reactive system, where the target is also expressed in normal tissues, 2.0 DAR conjugates were more efficacious than 3.5 DAR conjugates when dosed at matched payload concentrations in multiple xenograft models, suggesting that lower DAR can be an effective strategy to compensate for target-mediated drug disposition (TMDD).
Title: Utilizing a mouse cross-reactive model system to better understand antibody-drug conjugate pharmacokinetics, biodistribution and efficacy – abstract #229
Date: March 31, 2019
Time: 1:00-5:00 PM ET
Generation of a cross-reactive model system that utilized a chimeric anti-murine FRα antibody that binds both mouse and human FRα and can be conjugated to either maytansinoid or IGN payloads. This model system was predicted to have substantial TMDD due to normal tissue expression of FRα. The results showed that TMDD significantly affected the pharmacokinetics, biodistribution, and activity of the conjugate relative to a non-cross-reactive ADC, with lower ADC doses being more severely impacted than higher doses.
Additional information and full abstracts can be found at www.aacr.org.