Tightening of TCBs
a summary
High-grade serous ovarian carcinomas (HGSOCs) represent the
most common subtype of ovarian malignancies. Given the frequency of late-stage
diagnoses and high recurrence rates after standard care treatments, novel
therapies are needed to promote lasting responses. We investigated the
antitumor activity of bispecific antibodies containing CD3 T cells (TCBs)
directed against the HGSOC tumour antigen driven by the PAX8 LYPD1 lineage and
showed that anti-LYPD1 TCBs stimulate T cell activation and enhance T cell
inhibition of tumour growth in vivo. In those who express LYPD1. HGSOC. To
selectively target LYPD1-expressing tumour cells at high expression while
sparing cells with low expression, we ligated low-valent LYPD1 antigen-binding
fragments (Fabs) to an anti-CD3 scFv. In contrast to the monovalent LYPD1 TCB
antagonist (VHP354), the lower affinity LYPD1 TCB antagonist (QZC131) exhibited
antigen density-dependent selectivity and demonstrated tolerability in
cynomolgus monkeys at the maximum tested dose of 3 mg/kg... These data show
that LYPD1-directed bivalent TCBs have a compelling efficacy and safety profile
to support their use as a treatment for high-grade serous ovarian cancer. @smarttechpros
introduction
High-grade serous ovarian cancer (HGSOC) is the most
aggressive gynaecological malignancy. Because of the high rates of recurrence
after standard chemotherapy in combination with platinum ratings and late
presentation, the 5-year survival rate for patients diagnosed with HGSOC is
approximately 30%1,2. Inhibitors of poly(adenosine 5′-diphosphate-ribose)
polymerase (Barbie) for patients with BRCA or homozygous recombination
deficiency mutations improved overall survival by 30% 3. In addition, results
from early clinical trials showed modest clinical benefit in 10-15% of
monotherapy patients with apoptosis protein-1 (PD-1), suggesting that ovarian
cancer may be susceptible to certain types of immunotherapy. Despite these
recent advances in treatment, there is an urgent need for targeted therapies
for patients with advanced HGSOC.
Bispecific antibodies (TCB) against CD3 T cells have shown
remarkable efficacy in hematologic malignancies because these molecules can
activate and redirect cytotoxic T cells to tumour cells. Blinatumomab, which
targets CD19, is the first bispecific T-cell activator (BiTE) in clinical
development with demonstrated efficacy in relapsed/burn-resistant B-cell
precursors of acute lymphoblastic leukaemia and non-Hodgkin's lymphoma5,6,7.
BiTE and conventional bispecific CD3 antibodies targeting BCMA have shown
clinical response rates of 70% in patients with multiple myeloma. However, in
solid tumours, a narrow therapeutic indication has been a significant challenge
for the successful development of TCB against targets such as CEA, PSMA and
HER210,11,12. Despite these challenges, TCBs targeting tumour-restricted
antigens are emerging as effective forms of immunotherapy in advanced-stage
solid tumours with high unmet medical needs. Anti-DLL3xCD3 (AMG757) in small
cell lung cancer and anti-MUC16xCD3 (REGN4018) in advanced ovarian cancers
showed recent clinicopathological responses to the single agent.
Given the narrow therapeutic index of CD3 bispecific
antibodies, it is essential to identify targets with limited regular tissue
expression and high tumour selectivity. Lineage-specific targets have the
potential to reduce toxicity to non-tumour-derived ordinary tissue fractions.
PAX8 is a known transcription factor of the paired box and a strain driver of
HGSOC. ShrRNA and CRISPR knockout (KO) screens showed a strong dependence of
the PAX8 lineage on HGSOC. LYPD1 is a GPI-associated membrane protein with
intermediate cell surface expression in HGSOC. LYPD1 expression is restricted
to tissues of origin, such as the fallopian tubes and anterior pituitary,
making it a compelling TCB target for HGSOC17.
Here, we describe the transcriptional regulation of LYPD1
expression by PAX8 in HGSOC tumour cells. In addition, we demonstrate the
preclinical efficacy and non-primate human toxicity profile of QZC131, an
anti-LYPD1 TCB with bivalent low-affinity LYPD1 antigen-binding fragments
(Fabs) and a monovalent anti-CD3 scFv that selectively targets LYPD1. to the
intermediate level. @techgeeksblogger
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