On April 25, 2025 Precision Biologics, Inc. reported preclinical development and characterization of a novel ADC using its anti-core 2 O-glycans anti-human carcinoma mAb PB-223 will be presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025, on April 29th, 2025, McCormick Place Convention Center, Chicago, IL, USA (Press release, Precision Biologics, APR 25, 2025, View Source [SID1234652165]).
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Poster title: Development and characterization of an antibody-drug conjugate (ADC) utilizing PB-223, a novel monoclonal antibody (mAb) specifically targeting core 2 O-glycans on human carcinomas
The presentation of the poster will be made in person on the following date and location:
April 29th, 2025, 9am-12pm
McCormick Place Convention Center, Chicago, IL, USA
Session Title: Antibodies and Antibody-Drug Conjugates
Poster Section 36
Abstract Control Number 2878
BACKGROUND:
Antibody-drug conjugates (ADCs) represent a cutting-edge approach in cancer therapy. The three essential components of an ADC include: the mAb, the linker, and the cytotoxic payload. The mAb in current ADCs is usually designated to target specific tumor-associated antigens that are overexpressed on the surface of cancer cells.
Our ADC contains the following components:
The mAb: We used PB-223, an innovative mAb developed through affinity maturation of mAb NEO-102 (Ensituximab), a chimeric human IgG1 mAb that targets truncated core 2 O-glycans, specifically expressed by cancer cells and not by healthy tissues. The binding affinity of PB-223 for its target was improved, compared to NEO-102, by optimizing its VH and VL sequences through Fast Screening for Expression Biophysical Properties and Affinity. PB-223 demonstrated a binding affinity (KD) at least 4-fold lower than NEO-102, indicating stronger tumor binding. An immunohistochemistry analysis also revealed that PB-223 binds to a wider spectrum of tumor tissues compared to NEO-102, including not only colorectal, and pancreatic cancer, but also triple negative breast, prostate, kidney, head and neck, liver, and bladder cancer. Further experiments show PB-223 does not bind to normal tissues and that it can be internalized into human cancer cell lines expressing its target.
The payload: Monomethyl auristatin E (MMAE) was used as payload. MMAE is a potent antimitotic agent that inhibits cell division by blocking the polymerization of tubulin and is the most common ADC payload used to be linked to antibodies in clinical development for oncologic applications.
The linker: mc-vc-PABc was used as linker. PB-223 was conjugated to the linker-payload through a cysteine-based conjugation method.
STUDY PRESENTED AT AACR (Free AACR Whitepaper) 2025:
After development of the ADC we proceeded with its characterization, evaluating the following features:
DAR: The drug-to-antibody ratio (DAR) is crucial to predict the efficacy and safety of ADCs. It is generally believed that a DAR between 2 and 4 is the best choice for ADC drugs. Higher DAR may disrupt the pharmacokinetic properties of ADCs, while lower DAR significantly negatively affects the potency of ADCs. We developed three ADCs: PB-MMAE-2, PB-MMAE-5 and PB-MMAE-6. The DAR for these ADCs was 3.72, 3.92 and 4.15, respectively.
Binding of ADCs to cancer cells expressing core 2 O-glycans: flow cytometry was used for binding assessment of three ADC clones using the human ovarian cancer cell line OV-90 as the target. All three ADCs exhibit similar binding affinity to OV-90 compared to PB-223.
Killing of cancer cells: We evaluated the ability of all three ADC clones to kill OV-90 cells. All three ADCs effectively killed OV-90 cells (80% of cells were dead 5 days after treatment). We then chose one ADC clone, PB-MMAE-5, to test its ability to kill additional human cancer cell lines. Preliminary results show that PB-MMAE-5 can kill human prostate, triple positive and triple negative breast, lung, colon, pancreatic cancer cell lines.
Safety in vivo: We chose the ADC clone PB-MMAE-5 to test its toxicity in rats. The ADC PB-vcMMAE-5 in rats was administered intravenously at a concentration of 2.3 mg/kg as single dose. Animal body weight was measured at different time points until 14 days after ADC administration. The ADC PB-vcMMAE-5 was well tolerated in rats. No sign of distress nor loss of body weight were observed after administration.
Stability in human plasma: Stability of the ADC PB-vcMMAE-5 was evaluated in human plasma. PB-vcMMAE-5 ADC was incubated with male and female human plasma at concentration of 50 µg/mL and 100 µg/mL. Concentration in human plasma was detected by ELISA at 0h, 24h (1 day), 48h (2 days), 96h (4 days), 168h (7 days), 240h (10 days), 336h (14 days). The ADC was stable in human plasma (after 14 days, mean residual rate of PB-vcMMAE-5 ADC in human plasma was 23% for ADC at 100 µg/mL and 22% for ADC at 50 µg/mL).
Efficacy in vivo: The efficacy of the ADC PB-vcMMAE-5 was assessed in OV-90 subcutaneous xenograft model established in NOD-SCID mice. The ADC PB-vcMMAE-5 was administered intravenously at doses 1 mg/kg and 3 mg/kg, once per week for three weeks. Preliminary data suggest that PB-vcMMAE-5 exhibits anti-tumor activity in the NOD-SCID mice tumor model. Two days after the second dose of PB-vcMMAE-5 at 3mg/kg, treated mice showed a significant reduction in tumor volume compared to mice treated with an 1mg/kg dose of PB-vcMMAE-5, PBS or payload alone.
Findings from this study showed that PB-vcMMAE-5 can kill cancer cells expressing PB-223’s target, is not toxic, is effective in vivo, and is stable in human plasma, suggesting that PB-vcMMAE-5 has promising potential as a therapeutic option for a range of human malignancies expressing core 2 O-glycans.