# Novel targeted CAR-T multiple myeloma therapy

> **NIH NIH R43** · NOVAB, INC. · 2023 · $301,956

## Abstract

PROJECT SUMMARY
Multiple myeloma (MM), a malignancy of plasma cells (PCs), is responsible for over 12,500 deaths in the US and over
117,000 deaths worldwide annually. Over 91,000 individuals in the US and over 300,000 worldwide currently live with
MM. In spite of major therapeutic advances in the past two decades, MM remains incurable and most MM patients
succumb to the underlying malignancy. Recent therapies redirecting T cells via chimeric antigen receptor-T cells (CAR-Ts)
or bispecific antibodies that target B Cell Maturation Antigen (BCMA) have significantly improved survival of patients with
disease refractory to prior therapies. However, nearly all MM patients experience disease progression and become
refractory to these BCMA-targeted T cell therapies. There is therefore an urgent unmet need to develop new targets for
these potent T cell-directed MM therapies. This phase 1 SBIR application addresses that need with a novel monoclonal
antibody (mAb) designated MM3. MM3 belongs to a new class of antibodies, Variable Lymphocyte Receptor B (VLRB)
antibodies produced by the B cells of jawless vertebrates, lamprey and hagfish, and specifically binds to a distinctive form
of a well-validated MM therapeutic target, multimeric forms of the CD38 cell surface protein, with no detectable binding
to CD38 monomers. CD38 multimers are uniquely expressed by PCs and MM tumors, whereas CD38 monomers are
expressed by numerous other normal cell types, including NK and T cell immune effectors. CAR-T cells that utilize MM3 as
target recognition domain therefore avoid potential “on-target/off-tumor” toxicity associated with binding to monomeric
CD38, “fratricide” among CAR-T cells that express both monomeric CD38 and CAR antigen binding domains that bind
monomeric CD38, and depletion of NK and T cell immune effectors. Multimeric CD38 is highly expressed by the tumor
cells of relapsed-refractory MM (RRMM) patients refractory to proteasome and/or immunomodulator drugs. Although
downregulation of CD38 expression is one of several mechanisms of resistance to anti-CD38 mAb therapy, e.g.,
daratumumab, high levels of CD38 and multimeric CD38 expression return within 3 to 6 months of anti-CD38 mAb therapy
discontinuation, and MM tumor cells of over 87% of RRMM patients express high levels of CD38 multimers detected with
MM3. MM3 human CAR-T cells have been produced and shown with in vitro assays to direct CAR-T killing only to cells
that express multimeric CD38. This application will extend those results by: (1) producing MM3 CAR-T cells with T cell
preparations derived from healthy human volunteers and from patients relapsed following anti-BCMA CAR-T therapy and
evaluating in vitro target-specific activation and cytotoxicity against a MM cell line and autologous MM tumor cells from
anti-BCMA CAR-T relapsed MM patients, and (2) evaluating the in vivo anti-tumor efficacy of MM3 CAR-T cells with
MISTRG6 “humanized” mice engrafted with a human MM tumor cell line. These phase...

## Key facts

- **NIH application ID:** 10821186
- **Project number:** 1R43CA287584-01
- **Recipient organization:** NOVAB, INC.
- **Principal Investigator:** Lovick Edward Cannon
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $301,956
- **Award type:** 1
- **Project period:** 2023-09-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821186

## Citation

> US National Institutes of Health, RePORTER application 10821186, Novel targeted CAR-T multiple myeloma therapy (1R43CA287584-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10821186. Licensed CC0.

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