4 research outputs found
Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform
BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells
Background Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy.Method We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.Results BYON4228 is an antibody directed against SIRPα that recognizes both allelic variants of SIRPα in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRPγ that mediates interactions with CD47 as well, which are known to be instrumental in T-cell extravasation and activation. BYON4228 binds to the N-terminal Ig-like domain of SIRPα and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRPα and inhibits signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates macrophage-mediated and neutrophil-mediated killing of hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab. The silenced Fc region of BYON4228 precludes immune cell-mediated elimination of SIRPα-positive myeloid cells, implying anticipated preservation of myeloid immune effector cells in patients. The unique profile of BYON4228 clearly distinguishes it from previously reported antibodies representative of agents in clinical development, which either lack recognition of one of the two SIRPα polymorphic variants (HEFLB), or cross-react with SIRPγ and inhibit CD47-SIRPγ interactions (SIRPAB-11-K322A, 1H9), and/or have functional Fc regions thereby displaying myeloid cell depletion activity (SIRPAB-11-K322A). In vivo, BYON4228 increases the antitumor activity of rituximab in a B-cell Raji xenograft model in human SIRPαBIT transgenic mice. Finally, BYON4228 shows a favorable safety profile in cynomolgus monkeys.Conclusions Collectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRPα antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023
Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody–Drug Conjugate SYD985
Antibody–drug conjugates (ADCs)
that are currently on the
market or in clinical trials are predominantly based on two drug classes:
auristatins and maytansinoids. Both are tubulin binders and block
the cell in its progression through mitosis. We set out to develop
a new class of linker-drugs based on duocarmycins, potent DNA-alkylating
agents that are composed of a DNA-alkylating and a DNA-binding moiety
and that bind into the minor groove of DNA. Linker-drugs were evaluated
as ADCs by conjugation to the anti-HER2 antibody trastuzumab via reduced
interchain disulfides. Duocarmycin <b>3b</b>, bearing an imidazo[1,2-<i>a</i>]pyridine-based DNA-binding unit, was selected as the drug
moiety, notably because of its rapid degradation in plasma. The drug
was incorporated into the linker-drugs in its inactive prodrug form, <i>seco</i>-duocarmycin <b>3a</b>. Linker attachment to the
hydroxyl group in the DNA-alkylating moiety was favored over linking
to the DNA-binding moiety, as the first approach gave more consistent
results for in vitro cytotoxicity and generated ADCs with excellent
human plasma stability. Linker-drug <b>2</b> was eventually
selected based on the properties of the corresponding trastuzumab
conjugate, SYD983, which had an average drug-to-antibody ratio (DAR)
of about 2. SYD983 showed subnanomolar potencies against multiple
human cancer cell lines, was highly efficacious in a BT-474 xenograft
model, and had a long half-life in cynomolgus monkeys, in line with
high stability in monkey and human plasma. Studies comparing ADCs
with a different average DAR showed that a higher average DAR leads
to increased efficacy but also to somewhat less favorable physicochemical
and toxicological properties. Fractionation of SYD983 with hydrophobic
interaction chromatography resulted in SYD985, consisting of about
95% DAR2 and DAR4 species in an approximate 2:1 ratio and having an
average DAR of about 2.8. SYD985 combines several favorable properties
from the unfractionated ADCs with an improved homogeneity. It was
selected for further development and recently entered clinical Phase
I evaluation