About
Alpha Beta Therapeutics goal is to create novel therapies that arm tumor-associated macrophages to trigger cancer cell killing.
We have developed fully humanized antibodies (Patent Pending) that trigger Macrophage-Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC).
Mission

Develop human antibodies that potentiate immune destruction of cancer

Engineer anti-tumor antibodies that selectively engage and activate relevant tumor-localized effector cells

Can be used in a broad range of cancers including lung, pancreas, colon, breast, brain and kidney

Capable of targeting drug-resistant cancers and enhancing standard-of-care

Advance the knowledge that was created through the years of basic scientific development and prior clinical trials
Alpha Beta Therapeutics - Team

Integrin avβ3 mediates wound repair, remodeling
Epithelial cancer cells hijack this pathway to overcome stress
Epithelial cells use cell-cell and cell-matrix cues to “enforce boundaries”
- During a wound response, cells must rapidly gain the ability to “overcome boundaries”.
- Stress tolerance
- Lack of Cell/matrix attachment
- Hypoxia
- Inflammatory cells & cytokines
- Migration/invasion/proliferation
- De-differentiation
- Stress tolerance
- After wound repair, cells differentiate and return to an epithelial phenotype.
Epithelial to mesenchymal transition (EMT)
Mature epithelial cells lack avβ3, but it is upregulated by cellular stress, hypoxia inflammatory cytokines
- Gain of avβ3 is required for tissue remodeling and repair:
- Endothelial cells during angiogenesis
- Epithelial cells during wound repair
- Cardiomyocytes after ischemia
- Cancer cells “hijack” integrin avβ3
- Adaptive response to cancer therapy
- De-differentiated(mesenchymal state)
- Drives anchorage independence, metastasis, invasion, drug resistance, and cancer stemness
Highlights: Cheresh lab research on integrin avβ3
1990’s (Characterization of integrin avβ3)
Generation of LM609, the first monoclonal antibody to recognize the intact avβ3 heterodimer (PNAS, 1987)
Role of avβ3 on vascular endothelial cells:
- Fibrinogen binding during wound healing (Cell, 1989)
- Angiogenesis (Science, 1994)
- Ocular neovasculor disease (PNAS, 1996)
- Targeting vasculor avβ3 induces tumor regression (Cell, 1994)
Driver of invasive cancer cell phenotype:
- Melanoma (Cancer Metastasis Rev, 1991)
- Glioblastoma (JCI, 1991)
- Breast cancer (Clin Can Res. 1998)
Role of avβ3 In tissue remodeling:
- Osteoclasts (JBC, 1991)
- Wound repair (AJP, 1996)
- Ischemio (MP. 1996)
- Atherosclerosis (Cell Adhes Commun, 1998)
- Rheumatoid arthritis (JCI 1999)
Role in adenovirus infection (Cell, 1993)
2000’s (anti-avβ3 for cancer therapy)
Provided consultation to generate a fully humanized and affinity matured form of LW°, Vitaxin/Abegrin was tested in hundreds of cancer patients
Recent work (Role of avβ3 In cancer cells)
Integrin avβ3 promotes a more aggressive and dangerous cancer cell phenotype:
- Mesenchymal cell invasion (Moi Biol Cell, 2008)
- Anchorage independence & metastasis (Nat Med, 2009)
- Cancer stemness & drug resistance (Nat Cell Biol, 2014)
- KRAS addiction in lung/pancreas cancer (Can Disc, 2017)
- GLUT3 addiction in GBM (Cancer Cell, 2017)
2019 (Basis for ABT-l01 development)
- Co-enrichment of avβ3 with tumor-associated macrophages (TAMs) (Cancer Res, 2019)
- LM609 recruits TAMs tor tumor killing (Cancer Res, 2019)
Scientific rationale for targeting integrin avβ3
avβ3 is a driver of cancer progression, drug resistance, & sternness
Integrin avβ3 is linked to progression and metastasis across multiple cancer types

Melanoma
Vertical growth phase and lymph node adhesion (Albelda et al, Cancer Res, 1990; Nip et al, J Clin Invest, 1992)

Prostate
Bone metastasis (McCabe et al, Oncogene, 2007)

Breast
Bone metastasis (Takayama et al, Anticancer Res, 2005; Sloan et al, Breast Cancer Res, 2006; Felding-Habermann et al, PNAS, 2001)

GBM
Expressed at the tumor margin; role in invasion (Bello et al, Neurosurgery, 2001)

Lung
Poor outcome (Dingenanis et al, Molecular Cancer, 2010)

Pancreas
Lymph node metastasis, poor outcome (Hosotani et al, Pancreas, 2002; Desgrosellier et al, Nature Medicine, 2009)
Integrin avβ3 is enriched on drug-resistant and stem-like EGFR mutant lung cancer cells

KEY HIGHLIGHTS: Abegrin/etaracizumab/ MEDI-522
Clinical Track Record
- Good safety with no dose-limiting toxicity
- Some clinical activity in a range of cancers
- Patients were not selected for avβ3 expression on tumor cells
- Some trials combined with immunosuppressive agents
- Melanoma trial: Longer survival for [Abegrin] vs. [Abegrin + dacarbazine]
- Optimized for NK cell engagement, but not macrophages
Room for Improvement
- Re-engineer to promote macrophage engagement
- Do not combine with immunosuppressive agents
- Select patient populations with high avβ3 expression on tumor cells
- Cancers that are metastatic, drug-resistant, late-stage, KRAS addicted
Scientific rationale for engaging macrophages
avβ3+ tumor cells recruit macrophages, but not NK cells
Integrin avβ3 expression is sufficient to enrich for macrophages

Analysis of human cancer (TCGA datasets) shows co-enrichment of avβ3 with macrophages, but not NK cells

Anfi-avβ3 eliminates cancer drug resistance and circulating tumor cells (CTC) in mice
avβ3+ tumor cells recruit macrophages, but not NK cells
LM609 prevents acquired drug resistance in vivo

LM609 prevents the enrichment of β3 expression

LM609 prevents the emergence of circulating tumor cells

Anti-tumor activity of anti-avβ3 in mice depends on tumor associated macrophages (TAMs)
Mice treated with clodronate liposomes to deplete macrophages
