BVX001, a Bispecific ADC Targeting CD7-Positive AML with Favorable Toxicity Profile, Exhibits Significant Efficacy in Primary Patient Samples and PDX-Models

Background

Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy with limited treatment options. CD7-positive AML has emerged as an aggressive and treatment -resistant subtype of AML, with shorter overall survival lacking effective and safe targeted therapeutic approaches. BVX001 is a First-in-Class anti-CD33 x anti-CD7 bispecific antibody-drug conjugate (ADC) using auristatin MMAF as its payload. We present data on its favorable safety profile and compelling efficacy in two relevant pre-clinical models of the disease.

Objective

Evaluation of therapeutic impact and toxicity profile of BVX001. Specifically, assessment of BVX001 efficacy on heterogenous primary CD7-positive AML patient samples: age range 24-89 years, both sexes, broad target expression profile (40-92% double positive blasts) and mutational status (FLT3, IDH). Establish BVX001 efficacy in PDX models of AML and define safety and toxicity profile of ADC after repeat dosing in humanized mouse and non-GLP rat toxicity study at up to 55mg/kg, respectively.

Methods

PBMCs from four AML patient leukapheresis samples containing a variable fraction of CD7+/CD33+ double positive blasts were incubated to dose range of BVX001 (0.01 nM – 750 nM) for six days including isotype control ADC. Cell viability was assessed using CellTiter-Glo®. PDX models were established from two of the four AML patient samples by tail vein injection of 2x10e6 cells into sub-lethally irradiated immunocompromised NCG mice.

Engraftment rates were monitored by Flow Cytometry of bone marrow (BM) from surrogate mice. Once human CD45+ cell content was > 20%, mice were randomized in groups of 5 and subsequently treated for 4 weeks. Dose groups for BVX001 were 10 mg/kg (weekly), 6 mg/kg (weekly) and 3 mg/kg (twice weekly). Treatment effects on AML blasts were quantified by Flow Cytometry of BM at end of dosing.

Mouse model reconstituted and stably engrafted with human immune cell populations assessed on-target/off-tissue toxicity of BVX001 and impact on human immune cell populations monitored by Flow Cytometry. The toxicity profile of BVX001 was evaluated in a non-GLP rat tox study dosed weekly at 10, 30, and 55 mg/kg followed by necropsy at day 15. Detailed histopathological and hematological analyses assessed maximum tolerated dose (MTD), target organs of toxicity and their severity as well as blood chemistry biomarkers.

Results & Discussion

All AML patient samples showed dose-dependent sensitivity to BVX001 treatment with significant blast reduction seen across a diverse patient population including target expression levels, age & cytogenetics with IC₅₀ ranging from 0.186 to 104nM; 3 of the patient samples returned IC₅₀s of <10nM. No clear association between target expression levels and sensitivity to BVX001 was apparent. AML PDX models further underpin the specific efficacy of BVX001 in targeting AML blasts.

BVX001 showed highly favourable safety profile after two repeat doses at 10mg/kg once weekly (human equivalent dose 30mg/m²). No marked effect on major immune cell populations in BM was observed. In contrast, Mylotarg^® causes a potentially fatal reduction of healthy neutrophils after single dose (0.3mg/kg), linked to one of the leading causes of death in AML patients in the clinic.

Non-GLP rat tox study did not reach a MTD at 55mg/kg after 2 repeat weekly dosing. Toxicokinetic analysis showed dose-proportional systemic exposure with no drug accumulation nor gender differences. Histopathological observations across tissues were consistent with the profile of the MMAF-payload profile. No severe pathological changes were seen at any dose tested with marked observations only in the higher dose groups. Importantly, ocular toxicity was not observed at mid to low doses. BVX001 exhibited superior platform toxicity profile cf approved ADC using same conjugation/linker / payload (Blenrep™ - MTD_rat 20mg/kg mass difference adjusted) with a therapeutic window >35 compared to 14.5 for Blenrep™.

In conclusion, BVX001 – a First-in-Class bispecific ADC showed propitious efficacy and favorable safety profile, further supporting its potential as a therapeutic option for CD7-positive AML. The data presented here significantly strengthens the preclinical data package for BVX001, informing clinical dose selection and supporting progression to final IND-enabling studies and towards clinical studies.